Cell Proliferation and Its Regulation - UCSF Biochemistry ...

Katherine Hyland, PhD 

Cell Proliferation and Its Regulation 

(Biochemistry/Molecular Biology Lecture) 

OBJECTIVES 

• Describe the key properties of stem cells. 

• List the four phases of the cell cycle and describe what happens in each 

phase. 

• Name the four cyclin-Cdk complexes that drive the human cell cycle and 

explain how the timing of their function is regulated. 

• Diagram the pathway by which the G1 Cdk activates the G1/S Cdk. Describe 

the molecular events that take place at each step of the pathway, and explain 

why they are important for the proliferation of normal and cancer cells. 

• Name the two classes of Cdk inhibitors and the cyclin-Cdk complexes they 

inhibit. 

• Describe the general nature of cell signaling networks that allow cells to 

interpret information from numerous extracellular signals. 

• Describe three classes of receptor proteins in the plasma membrane, and 

explain how they transmit extracellular signals to the cell interior. 

• Diagram the pathway leading from the binding of epidermal growth factor 

(EGF) to the EGF receptor to activation of the cyclin D gene. Describe the 

molecular events that take place at each step of the pathway. 

• Describe the Wnt signaling pathway and its effect on cell proliferation. 

• Describe in molecular terms how TGFß inhibits cell division. 

• Describe how apoptosis can be triggered by either extracellular or 

intracellular signals. 

• Explain how the balance between pro-apoptotic and anti-apoptotic proteins 

determines whether a cell will die. 

• Explain how p53 causes cell cycle arrest and apoptosis. 

• Describe the spindle assembly checkpoint and the molecular function of the 

Mad2 protein. 

• Describe how selective proteolysis is achieved by the cell. 

KEY WORDS 

anaphase 

anaphase-promoting complex/cyclosome (APC/C) 

antimitogen 

APC (adenomatous polyposis coli) 

apoptosis 

ß-catenin 

Bcl-2 

caspase 

Cdk inhibitor 

cell cycle 

checkpoint 

chromosome segregation 

cyclin 

Mad2 protein 

MEK 

metaphase 

mitogen 

mitogen activated protein kinase (MAPK) 

mitotic spindle 

Myc 

p16 

p21 

p27 

p53 

progenitor cell 

proteasome 

35

Cell Proliferation and its Regulation 

KEY WORDS (Continued) 

cyclin-dependent kinase (Cdk) 

cytochrome c 

cytokinesis 

E2F transcription factor 

epidermal growth factor (EGF) 

Grb2 

growth factor 

GTPase-activating protein (GAP) 

GTP-binding protein (G-protein) 

guanine nucleotide exchange factor (GEF) 

Her2/neu 

kinetochore 

Rb protein 

Raf 

Ras 

receptor tyrosine kinase 

SH2 domain 

sister chromatid 

sister chromatid cohesion 

Sos 

spindle pole 

stem cell 

survival factor 

terminal differentiation 

transforming growth factor ß (TGFß) 

Wnt protein 

Optional reading: 

Alberts et al. Molecular Biology of the Cell; 5th Edition, Garland Science, 2008. 

Chapter 17: Cell Cycle; Chapter 18: Apoptosis. 

Kumar, Abbas, Fausto and Mitchell. Robbins Basic Pathology; 8th Edition, Elsevier/Saunders, 

2007. Chapter 6 - Neoplasia: Cell Cycle, pp 188-198. 

I. INTRODUCTION 

Cell proliferation produces two cells from one, and it requires cell growth followed by 

cell division. Uncontrolled cell proliferation is a hallmark of cancer. As described in the 

overview lecture of cancer biology, multiple mutations that accumulate in somatic cells 

over many years eventually remove an elaborate set of controls that would otherwise 

prevent cancer cells from dividing unchecked. In this lecture, we will focus on the normal 

mechanisms that allow nearly all of the billions of cells in our body to proliferate only 

when they should. These mechanisms are subverted in cancer cells, and it is impossible to 

understand cancer without first understanding the controls that keep the vast majority of 

the 10 14 cells (100,000 billion cells) that form the human body from misbehaving. 

In normal tissues, cell proliferation is generally restricted to cells that replenish the tissue. 

Most tissues are thought to contain stem cells that have this replenishment function 

(Figure 1). Stem cells are self-renewing cells that can divide asymmetrically to yield a 

new stem cell and a progenitor cell. Progenitor cells may or may not undergo further 

divisions, ultimately leading to terminal differentiation. Once cells have terminally 

differentiated, they have a specialized function and are no longer dividing. Most tissues 

are made up of such non-dividing cells. Thus proliferation is normally tightly controlled 

so that only particular cells in the body are dividing. 

Cell number is dependent not only on cell proliferation, but also on cell death. 

Programmed cell death, or apoptosis, is the process by which excess or damaged cells in 

the body are removed. Apoptosis is an extensive, ongoing process in our bodies. It is the 

balance between the production of new cells and cell death that maintains the appropriate 

36


Stem Cell (self-renewing) 

Progenitor (Dividing) 

Figure 1. Stem Cells. Stem cells are 

self-renewing cells. They can divide 

asymmetrically to produce a new 

stem cell (indicated by a circle) and a 

progenitor cell. Progenitor cells divide 

to produce cells that undergo terminal 

differentiation to produce the mature 

cells that make up a tissue or organ. 

Terminally Differentiated 

Cells (Non-Dividing) 

number of cells in a tissue (referred to as homeostasis). Apoptosis is also a key 

mechanism by which cancer-prone cells are eliminated. Both normal apoptotic processes 

and normal cell mechanisms that control proliferation usually need to be altered to 

produce enough abnormal cell proliferation to cause cancer. 

II. 

THE CELL CYCLE 

Cell division occurs in defined stages, which together comprise the cell cycle. In terms 

of the genetic material, cells must replicate their chromosomal DNA once every cell 

cycle and segregate the sister chromatids produced by DNA replication to yield two 

genetically identical daughter cells (Figure 2). During DNA replication, cohesion 

proteins attach the replicated sister chromatids to each other, holding them together. 

This sister chromatid cohesion is critical for the subsequent alignment of each pair of 

sister chromatids on the mitotic spindle (see below), and it is therefore essential for the 

subsequent segregation of one (and only one) chromatid of each pair into each of the two 

daughter cells. 

14 

The cell division cycle is broken up into four stages: G 1 

, S, G 2 

and M (Figure3). 

DNA replication occurs during S (“synthesis”) phase. DNA packaging, chromosome 

segregation and cell division (cytokinesis) occur in M (mitosis). S phase and M phase 

are separated by Gap phases. G 

Thompson & Thompson GENETICS IN MEDICINE 1 

is the gap between M and S. Cell growth is one of the 

important events of G1. The transition from G1 to S is the critical control point in the cell 

M 

G 2 

(2-4 hr) 

G 1 

(10-12 hr) 

S 

(6-8 hr) 

Telomere 

Telomere 

Sister chromatids 

Centromere 

Figure 2-9 ■ A typical mitotic cell cycle, described in the 

text. The telomeres, the centromere, and sister chromatids 

are indicated. 

37 

spend a long time, days or years, in G 1 . In fact, some 

cell types, such as neurons and red blood cells, do not 

divide at all once they are fully differentiated; rather, 

The two sister chromatids are held together physically 

at the centromere, a region of DNA that associates with 

a number of specific proteins to form the kinetochore. 

Figure 

This complex 

2. The chromosome 

structure serves 

cycle. 

to attach 

A key 

each chromosome 

to of the cell microtubules division is of the the duplication mitotic spindle and to 

purpose 

of govern the genetic chromosome material movement carried on during mitosis. DNA 

chromosomes synthesis during and S its phase accurate is not synchronous segregation throughout 

such all chromosomes that each daughter or even cell within acquires a single one chromosome; 

copy rather, of each along chromatid. each chromosome, (Reproduced it begins at hundreds 

from to thousands Thompson of & sites, Thompson called origins Genetics of DNA in replication. 

Medicine, Individual 7th chromosome edition, Nusbbaum, segments have et al, their own characteristic 

2007, time with of permission replication from during Elsevier.) the 6- to 8-hour 

p.14, 

S phase. 

By the end of S phase, the DNA content of the cell 

has doubled, and each cell now contains two copies of 

the diploid genome. After S phase, the cell enters a brief 

stage called G 2 . Throughout the whole cell cycle, ribonucleic 

acids and proteins are produced and the cell 

gradually enlarges, eventually doubling its total mass 

before the next mitosis. G 2 is ended by mitosis, which 

begins when individual chromosomes begin to condense 

and become visible under the microscope as thin, 

extended threads, a process that is considered in greater


Figure 3. The cell cycle. Reproduced 

with permission from Alberts et 

al. Molecular Biology of the Cell. 

Garland Publishing, 2002. 

cycle. G2 is the gap between S and M, and provides time for proofreading to ensure DNA 

is properly replicated and packaged prior to cell division. G0 or quiescence occurs when 

cells exit the cell cycle due to the absence of growth-promoting signals or presence of 

prodifferentiation signals. Ordered progression through each phase is intricately regulated 

through both positive and negative regulatory signaling molecules. The G 1 

, S, and G 2 

phases comprise interphase, which accounts for most of the time in each cell cycle. 

The M phase, mitosis, is relatively short (approximately 1 hour of a 24 hour cell cycle). 

Mitosis is itself divided into several steps, described below. (For a review of mitosis, see 

the Mitosis and Meiosis online module on iROCKET.) 

1. Assembly of the mitotic spindle: At the very beginning of M phase (called 

prophase), the chromosomes condense while the cytoplasmic microtubules are being 

reorganized to build a bipolar mitotic spindle. Its purpose is to accurately segregate 

the two sister chromatids to opposite poles of the cell. 

2. Steps leading to metaphase: The nuclear envelope then breaks down, allowing the 

sister chromatids, which are attached to each other through sister chromatid cohesion, 

to become linked to the microtubules via attachment sites on each chromatid called 

kinetochores. Kinetochores are protein-DNA complexes in which proteins that 

can capture microtubules are held tightly by DNA sequences at the centromere 

on each sister chromatid pair. The other end of a spindle microtubule is attached 

to a centrosome (the major microtubule organizing center in the cell, also called 

the spindle pole body), which has duplicated by this time to form the two spindle 

poles. Because the two kinetochores on each pair of sister chromatids are attached 

to opposite spindle poles, they are under tension due to pulling forces that are 

attempting to move them to opposite poles. Eventually, the balance between these 

forces causes each chromosome to line up near the center of the spindle, which marks 

the metaphase stage of mitosis (Figure 4). 

3. Anaphase: After all the chromosomes achieve bipolar attachment to spindle 

microtubules in metaphase, sister chromatid cohesion is rapidly dissolved. As a 

result, the pulling forces of the microtubules cause the two sister chromatids to move 

rapidly to the opposite poles (Figure 5). 

4. Cytokinesis: After sister chromatids segregate to opposite poles, cells physically 

divide into two daughter cells through a process that involves pinching in of the 

plasma membrane (Figure 6). 

38


Figure 4. The mitotic spindle at metaphase. All of the chromosomes are lined up at the equator of 

the spindle. Reproduced with permission from Alberts et al. Molecular Biology of the Cell. Garland 

Publishing, 2008. 

Figure 5. Anaphase. Only three pairs of sister chromatids are shown; however, in a diploid cell, 

this occurs simultaneously for all 46 human chromosomes (that is, for 46 pairs of sister chromatids). 

(Reproduced with permission from Alberts et al. Molecular Biology of the Cell. Garland Publishing, 2008.) 

Figure 6. Cytokinesis. After the two sister chromatids are segregated to opposite poles, cells undergo 

cytokinesis by an organized pinching in of the plasma membrane. (Reproduced with permission from 

Alberts et al. Molecular Biology of the Cell. Garland Publishing, 2008.) 

39


III. 

CELL CYCLE CONTROL: ACTIVATORS and BRAKES 

How is the cell cycle controlled The mechanisms of regulation can be broken down into 

two parts: First, how is the cell cycle regulated so that the different phases occur in the 

correct order Second, how do extracellular signals activate or inhibit the cell cycle This 

section addresses the first question, the next section (IV) addresses the second. 

Not until the 1980s was it discovered that a special regulatory system acts like the 

controller on a washing machine to drive the cell through each of its stages. This 

regulatory system is more than a billion years old, and most of its central components 

are essentially the same in single-celled eukaryotes such as yeasts and humans. This has 

made it possible to use the readily accessible yeast cell to dissect many of the details that 

underlie the normal regulatory mechanisms that control the growth of the cells in our 

bodies. 

A. Cyclin Dependent Kinases: The core activators of the cell cycle control system. 

The events that occur in each part of the cell cycle are carried out by specific 

proteins, and these proteins must be synthesized or activated at the correct time in the 

cycle. For example, before DNA synthesis can begin, the enzymes that produce the 

nucleotides used in DNA synthesis must be activated. This occurs late in G1 phase. 

(Remember Nucleotide Metabolism See lecture from M&N.) 

Cell cycle progression is positively regulated by a family of protein kinases called 

cyclin-dependent kinases (Cdks), which function to turn specific proteins on and off 

at appropriate times in the cell cycle. Like other protein kinases, Cdks turn proteins 

on or off by phosphorylating them. Each cyclin-dependent kinase has two subunits 

- a kinase subunit (the Cdk catalytic subunit) and a cyclin subunit (Figure 7). As a 

monomer, the Cdk has no enzymatic activity; activation requires association with a 

cyclin protein, which functions as an allosteric activator. 

Cyclins were first identified as key cell-cycle regulators when it was observed that 

they undergo a cycle of synthesis and regulated destruction during each cell cycle. 

There are several different Cdks and a number of cyclins. The kinase subunits 

are present throughout the cell cycle, while the cyclin subunits are produced and 

degraded at specific times in the cell cycle, thus providing temporal regulation of the 

cyclin-Cdk complex. As the cyclin subunit is produced, it binds to the kinase subunit 

and activates it. The cyclin subunit also targets its kinase partner to specific protein 

substrates. The key cyclin-Cdk complexes that drive the human cell cycle are listed in 

Table I. 

The cell cycle can be viewed as a Cdk cycle (Figure 8). Activation of G1-Cdks 

by cyclin D turns on the events that occur in the early phase of G1. One of these is 

synthesis of cyclin E. As cyclin E is made, it binds to Cdk2, forming G1/S-Cdk. As 

the G1/S-Cdk activity accumulates to a critical threshold, it triggers the transition 

from late G1 into S phase. Cyclin A is made in S phase. It also binds to Cdk2, 

forming the S-Cdk that is required for DNA synthesis. Cyclin B is made during S 

phase and G2. As it is made, it binds to Cdk1 forming M-Cdk. When M-Cdk reaches 

a threshold activity, it triggers the transition from G2 into the prophase stage of 

mitosis. 

40


Figure 7. Cyclin-dependent 

kinases (Cdks). Cdks are 

the key regulators of the cell 

division cycle in organisms as 

diverse as baker’s yeast and 

humans. Cyclin-dependent 

kinases have two subunits, the 

kinase (often simply called the 

Cdk) and a regulatory protein 

called a cyclin. 

Table I. The four key cyclin-Cdks that drive the cell cycle 

Figure 8. The cell cycle as a Cdk cycle. Different phases of the cell cycle are driven by different cyclin- 

Cdk complexes. In this simplified view, only a G1/S-Cdk, a S-Cdk and a M-Cdk are shown. These act in 

sequence, as each cyclin protein is produced, to program the following critical events: the G1-S transition 

known as Start, S phase (DNA synthesis), and the start of M phase (mitosis). In addition, as described 

in the text, a G1-Cdk activated by cyclin D phosphorylates the Rb protein to produce cyclin E, which is 

required for G1/S-Cdk activity. Note that the activity of each Cdk disappears rapidly at a specific time 

in the cell cycle (as the specific cyclin protein is degraded). The APC/C is a large protein complex that 

controls a proteolytic process required for the separation of sister chromatids at anaphase. (Reproduced 

with permission from Alberts et al. Molecular Biology of the Cell. 5th Edition, Garland Publishing, 2008; 

Fig. 17-16, p. 1062) 

41


B. G1 regulation: How the G1-Cdk turns on the G1/S Cdk 

During G1, cells prepare for DNA replication. They must synthesize proteins 

necessary to replicate their genome, and then assemble the various components of 

the DNA replication machinery onto the origins of replication. This is coordinated 

with nutrient and growth factor availability to ensure the cell is in an environment 

that supports cell division. The G1 phase of the cell cycle is unique in that it 

represents the only time where cells are sensitive to signals from their extracellular 

environment. Cells require growth factor-dependent signals up to a point in late G1, 

referred to as the “restriction point” or Start, after which the transition is made into S 

phase. The transition between early G1 and late G1 (“Start”) illustrates one way that 

cyclin-dependent kinases regulate the progression of the cell around the cell cycle. 

This is a crucial control point that is often dysregulated in cancer. 

In order to move from early G1 to late G1, the cell must synthesize cyclin E. 

Transcription of the cyclin E gene requires a transcription factor called E2F. In 

cells that are not proliferating and in cells that are in early G1, the E2F transcription 

factor is bound to the promoter for the cyclin E gene, but it is inhibited by a protein 

that binds it, called Rb. (Rb stands for Retinoblastoma, a childhood tumor of the 

retina – more on this in the Tumor Suppressor and Oncogene lecture). Rb is a nuclear 

phospho-protein that plays a key role in regulating the cell cycle. It exists in an active 

underphosphorylated state and an inactive hyperphosphorylated state. In its active 

state, Rb serves as a brake that prevents advancement of cells from G1 to S phase. 

When G1-Cdk activity increases near the middle of G1, G1-Cdk phosphorylates the 

Rb protein and inactivates it (Figure 9). Inactive phosphorylated Rb releases from 

E2F and allows transcription of the cyclin E gene to take place. The cyclin E protein 

binds to the Cdk2 kinase to form the G1/S-Cdk. E2F also transcribes a number of 

other genes important for S phase, including the genes for DNA polymerase and 

thymidylate synthase. 

A. Molecular Events B. Control Relationships 

G1-Cdk OFF 

Cdk4-cyclin D (G1-Cdk) 

Rb 

E2F 

promoter 

cyclin E gene 

OFF 

Rb 

E2F 

G1-Cdk ON 

Rb 

P 

Cdk2 

cyclin E 

E2F 

promoter 

cyclin E gene 

ON 

Cdk2-cyclin E (G1/S-Cdk) 

Figure 9. How the G1-Cdk activates the G1/S-Cdk. The G1-Cdk (Cdk4-cyclin D) phosphorylates 

the Rb (Retinoblastoma) protein releasing it from transcription factor E2F. E2F can now activate 

transcription of cyclin E, which in turn results in the production of cyclin E protein and formation of 

the G1/S Cdk. In describing signaling systems, it is common to use an arrow to indicate an activation 

and the T-shaped symbol to indicate an inhibition. 

42


Importantly, the production a cyclin E, and thus CDK2-cyclin E activity, represents 

the transition from mitogen-dependent to mitogen–independent cell cycle progression 

(or passage through “start”), irreversibly committing the cells to enter S phase. Once 

cells enter S phase, they are committed to divide without additional growth factor 

stimulation. As we will discuss in later lectures, cells that acquire mutations that 

obviate the need for mitogen- dependent signals will bypass this crucial control point. 

C. Brakes on the cell cycle: Cdk inhibitors 

The Rb protein can be viewed as a “brake” on the cell cycle because it prevents the 

transcription of the gene for cyclin E by inhibiting E2F. Three other proteins that act 

as “brakes” on the cell cycle are the Cdk inhibitors p16, p21, and p27. These act by 

binding directly to Cdk-cyclin complexes and blocking their protein kinase activity 

(Figure 10). 

Cdk inhibitors fall into two classes: specific and general. The Ink4 (inhibitors of 

Cdk4) family of proteins, including p16, bind exclusively to and inhibit the G1 Cdks, 

Cdk4/6-cylin D. The Cip/Kip family of Cdk inhibitors, including p21 and p27, bind 

to a broad range of Cdk-cyclin complexes, shutting off the cell cycle at multiple 

points. Functionally, p21 and p27 appear to mainly inhibit Cdk2 complexes. As will 

be discussed in the Tumor Suppressor Gene and Oncogene lecture, alterations in 

these inhibitor proteins play an important role in cancer. 

Why is the cell cycle controlled by both activators (e.g. cyclins) and inhibitors (e.g. 

Rb, p16, p21, p27) As we will see, it helps each cell to respond to multiple inputs, 

so that it enters the cell cycle only when the correct combination of conditions are 

present. The control of cycle entry by both growth activating and growth inhibiting 

signals is part of a “fail-safe” system for insuring that cell proliferation only occurs 

when it is useful to a multicellular organism like ourselves. Without a complex 

control system of this type, humans could not exist, because we would all get cancer 

at a very early age (probably in utero). 

Figure 10. How Cdk inhibitors bind to and inactivate Cdks. (Reproduced with permission from Alberts 

et al. Molecular Biology of the Cell. Garland Publishing, 2008. 

43


IV. 

CONTROLLING PROLIFERATION: MITOGENS, ANTI-MITOGENS, and 

CELL SIGNALING 

A. General Principles of Cell Signaling 

Cell signaling processes are central to all of human biology and medicine. Although 

the details of cell signaling pathways can become very complex, the big picture of 

cell signaling (e.g. transmitting information from the extra-cellular environment 

into the cell so it can respond appropriately) is straightforward. Signaling 

pathways are built from a limited set of molecules and molecular mechanisms (e.g. 

phosphorylation or proteolysis) that allow for communication within and between 

cells. The underlying molecular mechanisms used in signaling pathways show a 

number of common properties. In particular, they allow signaling proteins to undergo 

switch-like activation from an inactive to an active state (for example by receptor 

clustering, GTP-binding to Ras proteins, and stabilization of β catenin, as described 

below) and they can also be readily reversed (e.g. by receptor down-regulation, 

hydrolysis of bound GTP, and β catenin degradation). Dr. Fulton introduced the 

subject of signaling last year, and it is important to review that material for this block 

(see lectures on Protein Function and Signaling from Prologue). The introductory 

lectures focused on one of the two major classes of cell surface receptor proteins 

present in all cells: the G-protein-linked receptor family. The other major class is 

referred to as the enzyme-linked receptor family. This class includes receptors linked 

to protein kinases, which fall into two subgroups: the receptor tyrosine kinases 

(RTKs) and the receptor serine/threonine kinases. An example of each is discussed 

below. 

B. Mitogens and Anti-Mitogens 

Non-dividing cells exist in phase called G0 (G zero). G0 cells can re-enter the cell 

cycle in G1 when stimulated by mitogens, which are extracellular proteins that 

stimulate cell proliferation by directly controlling the entry of cells into the cell 

cycle. (For historical reasons, mitogens are often loosely referred to as growth 

factors. Although it is best to reserve the latter term for those signaling molecules 

that actually induce cell growth, i.e. the increase in cell mass, these terms are often 

used interchangeably). Conversely, cells can be arrested in G1 via the action of 

Ligand 

Binding 

Domain 

Kinase 

Domain 

Tyrosine 

residue 

EGF 

P SH2 

SH3 

Grb2 

(adaptor protein) 

Sos 

Figure 11. Activation of the Epidermal 

Growth Factor (EGF) receptor tyrosine 

kinase. EGF binds to the EGF receptor through 

an extracellular ligand binding domain, leading 

to dimerization of the receptor. Dimerization 

causes one subunit to phosphorylate the other 

(transphosphorylation) on specific tyrosine 

residues. The SH2 domain of the Grb2 adaptor 

protein then binds to the region of the EGF 

receptor containing the phosphorylated 

tyrosines. Grb2 in turn, uses its second 

common protein domain, called SH3, to bind 

to another protein called Sos. Grp2 is known 

as an adapter protein, since it function to hold 

two other proteins together. Sos is a member 

of a large family of proteins that regulate G 

proteins (GTP-binding proteins) by causing the 

exchange of a tightly bound GDP molecule for 

GTP (see Figure 14). 

44


anti-mitogens (proteins that inhibit the activity of mitogens). Many mitogens and a 

smaller number of anti-mitogens are known. We will discuss one example of each: 

the mitogen epidermal growth factor (EGF) and the anti-mitogen transforming 

growth factor ß (TGFß). The receptors for these factors are both enzyme-linked 

receptors. The EGF receptor, or EGFR, is an example of a receptor tyrosine kinase 

(RTK), and the TGFß receptor is a receptor serine/threonine kinase, 

What are the normal functions of these factors One function of EGF is to promote 

wound healing. After a wound is formed, epidermal and inflammatory cells secrete 

EGF and other growth factors. It signals cells at the margins of the wound to 

proliferate so that the wound may be healed. TGFß acts as a brake to this process so 

that the proliferation is coordinated with other aspects of wound healing. 

C. The EGF Signaling Pathway 

The EGF receptor belongs to the ErbB family of RTKs, which has four members 

capable of homo– or heterodimerization. Each receptor heterodimer can respond to a 

distinct set of extracellular ligands and has different intracellular signaling properties. 

Interestingly, another member of the ErbB family, the ErbB2 receptor (also called 

HER2/neu) lacks intrinsic growth factor-binding activity. Consequently, in normal 

cells HER2/neu must function as part of a heterodimer with another ErbB family 

member, such as EGF. (More about HER2/neu and its role in breast cancer in later 

lectures.) 

EGF functions by binding to the extracellular domain of EGF receptor, a cell 

surface protein with a single transmembrane domain (Figure 11). The cytoplasmic 

domain of the receptor is the protein tyrosine kinase. When EGF binds to its 

receptor, the receptor forms a dimer in which one subunit phosphorylates the other 

(transphosphorylation) on particular tyrosine residues in the cytoplasmic part of the 

receptor. These phosphorylated tyrosines serve as binding sites for other cytoplasmic 

proteins that contain special domains, called SH2 domains. SH2 domains specifically 

recognize phosphorylated tyrosines and the adjacent amino acids. One protein that 

binds to phosphotyrosine residues in the EGF receptor is an adaptor protein called 

Grb2. Grb2, in turn, recruits a protein called Sos. Thus binding of EGF to the EGF 

receptor recruits both Grb2 and Sos to the intracellular portion of the receptor. 

Sos 

GDP 

GTP 

Ras-GDP 

Ras-GTP 

inactive 

active 

GAP 

GTPase-activating protein 

45 

Figure 12. Sos is a guanine 

nucleotide exchange protein (GEF) 

that activates the Ras protein. Ras 

is a monomeric GTP-binding protein 

that is only active in its GTP-bound 

form. In its GDP bound form, Ras 

is inactive. When Sos binds to Grb2 

at the EGF receptor, it is brought 

close to membrane-bound Ras-GDP 

molecules, causing the Ras to release 

its GDP and bind a GTP in its place. 

A second common type of protein is 

a GTPase-activating protein (GAP), 

which inactivates Ras by promoting 

its GTP hydrolysis. The cell contains 

hundreds of monomeric GTP-binding 

proteins that serve to regulate many 

different functions. Each is regulated 

in a similar way by GEFs and GAPs.


MEK 

inactive 

Ras-Raf 

MAPK 

inactive 

MEK-P 

active 

MAPK-P 

active 

Target Target-P 

inactive 

active 

Figure 13. Ras activates the MAP 

kinase cascade. Ras-GTP binds 

directly to Raf, which activates its 

kinase activity. Raf phosphorylates 

a kinase called MEK (also called 

MAP kinase kinase). After it has 

been phosphorylated by Raf, MEK 

phosphorylates MAP kinase (mitogen 

activated protein kinase, MAPK). 

Active MAPK then phosphorylates 

its target proteins, including 

transcription factors, stimulating the 

entry of the cell into the cell cycle. 

Sos is a guanine nucleotide exchange factor (GEF). It acts on a small monomeric 

GTP binding protein, Ras. The Ras protein is bound to the inner surface of the 

plasma membrane. Like the G-proteins discussed by Dr. Fulton in the Prologue, Ras 

can exist in two states: an inactive state in which GDP is bound, and an active state 

in which GTP is bound. Sos activates Ras by promoting the release of its GDP and 

binding of GTP (Figure 14). Recruitment of Sos to the plasma membrane where Ras 

is located results in the activation of Ras. Ras can be returned to its inactive form 

through the hydrolysis of GTP to GDP. This step occurs when a GTPase-activating 

protein (GAP) binds Ras and induces the hydrolysis of its GTP (see Figure 12). 

In its GTP-bound (active) state, Ras turns on a protein kinase cascade, in which 

protein kinases sequentially activate each other through phosphorylation (Figure 

13). Active Ras binds to and activates a protein kinase called Raf. In turn, Raf 

phosphorylates and activates another kinase called MEK (MAP kinase kinase). 

MEK in turn phosphorylates and activates mitogen-activated protein kinase, MAP 

kinase. This chain of phosphorylation events is called the MAP kinase cascade. 

MAP kinase phosphorylates gene-specific transcription factors in the cell nucleus 

that bind to the promoters of genes and promote cell proliferation. One important 

transcription factor that is up-regulated by the MAP kinase cascade is Myc, which is 

the product of the c-MYC gene. 

One of the targets of transcription factors that are activated by the MAP kinase 

cascade is the cyclin D gene. Thus, a multi-tiered pathway connects the presence of 

a mitogen (EGF) outside the cell to increased expression of a key component of the 

cell cycle control machinery (the cyclin D gene) in the nucleus (Figure 14). Increased 

expression of the cyclin D gene leads to the activation of G1-Cdk, pushing the cell to 

proliferate, as explained previously. 

MAPK 

Transcription 

Factors 

(e.g. Myc) 

cyclin D 

Figure 14. Activation of MAP kinase leads to the transcription of cyclin D. MAPK phosphorylates 

transcription factors. This in turn leads to the transcription of the Myc gene, which itself encodes a 

transcription factor for the cyclin D gene. 

46


D. Wnt signaling 

The Wnt proteins are mitogens analogous to EGF. They function in a signaling 

pathway that regulates cell proliferation by controlling proteolysis of a key signaling 

protein (Figure 15). The Wnt signaling pathway plays a central role during embryonic 

development, and also serves important functions in adults. For example, Wnt 

signaling is necessary for the proliferation of stem cells in the proliferative zones 

in the gut epithelium (the crypts that lie between the microvilli of the epithelium) 

(Figure 16). Colon cancer is almost invariably associated with the hyperactivation of 

this pathway in an early step of tumor evolution. 

As illustrated in Figure 15, Wnt proteins bind to a cell surface receptor called 

Frizzled. Frizzled controls the stability of a protein called ß-catenin, which functions 

together with a protein called TCF to form a transcription factor that activates the 

promoter of the cyclin D gene. 

When Wnt is bound, Frizzled turns off a protein kinase called GSK-3. GSK-3 

normally functions to promote the degradation of ß-catenin, thus preventing it from 

activating the cyclin D promoter. Phosphorylation of ß-catenin by the protein kinase 

GSK-3 results in its degradation. However, GSK-3 can only phosphorylate ß-catenin 

when ß-catenin is bound to a protein called APC (adenomatous polyposis coli). 

Thus, APC is necessary to hold ß-catenin in check, and loss or inactivation of APC 

is associated with development of colorectal cancer (as described in later lectures). 

(Note: this APC protein is not to be confused with APC/C, the anaphase promoting 

complex/cyclosome, to be described later in this lecture.) 

Wnt 

Frizzled 

GSK-3 

P 

P 

b-catenin 

APC 

b-catenin 

APC 

degradation 

TCF 

APC 

b-catenin 

TCF 

cyclin D 

Figure 15. The Wnt signaling pathway (see text for details). 

47


microvillus 

microvillus 

high 

Expression 

of APC 

crypt 

(proliferating 

stem cells) 

Figure 16. Expression of the APC gene in the gut epithelium. Shown is a 

schematic of a microvillus in the gut epithelium showing the zone of proliferation 

(crypts) and the gradient of expression of the APC gene, whose protein product 

inhibits Wnt signaling. 

low 

Once GSK-3 is inhibited by Frizzled, ß-catenin is no longer degraded, allowing it to 

associate with TCF and activate the cyclin D promoter and promote cell proliferation. 

Thus, Wnt signaling promotes cell proliferation through the effect of ß-catenin on 

cyclin D production. 

While Wnt proteins are the extracellular growth factors that activate this pathway, 

cells also control the pathway from within the cell by varying the transcription 

of the APC gene, whose protein product inhibits the Wnt signaling pathway. For 

example, in the epithelium of the colon, there exists a gradient of APC expression 

that is highest in the terminally differentiated nondividing cells in the microvilli and 

lowest in the proliferating stem cells in the crypts (see Figure 16). (More about the 

role of APC in colon cancer to come in lectures on Colon Cancer and Familial and 

Hereditary Cancer Syndromes.) 

E. TGFß-Smad: An anti-mitogenic pathway 

Like EGF, TGFß is an extracellular protein that binds a cell surface receptor. 

However, instead of causing cell proliferation, this molecule causes cells to 

arrest their cell cycle and enter G0. How does this occur The TGFß receptor is 

a transmembrane serine/threonine kinase. Upon binding to TGFß, the receptor 

phosphorylates proteins in the cytoplasm called Smads (Figure 17). Once 

phosphorylated, Smad proteins then enter the nucleus and function as transcription 

factors to turn on specific target genes. A key gene turned on by TGFß is the Cdk 

inhibitor p21 discussed above. The activation of p21 blocks G1-S transition by 

inhibiting Cdk2-Cyclin E/A, leading to the arrest of the cell cycle. Thus, TGFß 

arrests cell division by turning on transcription of the gene for a Cdk inhibitor. 

V. APOPTOSIS 

As previously explained, the number of cells in a tissue is controlled not only by cell 

proliferation, but also by programmed cell death, or apoptosis. For a tissue to stay the 

same size, cell proliferation and cell death must be perfectly balanced. Apoptosis plays 

important roles both during development and in mature tissues. For example, during 

development of a limb, tissue present between the digits must be removed. This occurs 

through localized apoptosis (Figure 18). 

48


TGF 

Smad 

Smad-P 

Smad-P 

promoter 

kinase 

domain 

p27 gene 

TGF receptor 

plasma 

membrane 

p21 

Cdk4-cyclin D 

Cdk2-cyclin E 

Cdk2-cyclinA 

Figure 17. How TGFß 

arrests cell division. TGFß 

binds to the TGFß receptor. 

Binding of TGFß activates 

the receptor’s intracellular 

protein kinase domain, 

leading to phosphorylation of 

Smad proteins on serine and 

threonines. Phosphorylated 

Smads enter the nucleus and 

bind to promoters of genes to 

control transcription. A key 

target is the p21 gene. The 

p21 protein in turn inhibits 

cyclin E/A- cdk2 complexes, 

thus leading to cell cycle 

arrests. 

nucleus 

As described in the Prologue block, the process of apoptosis requires the activation of a 

special class of proteases inside the cell known as caspases. Caspase molecules normally 

exist as inactive procaspase molecules in the cell. Procaspase activation is carefully 

controlled, so that the cell only kills itself when this is appropriate for the success of the 

organism as a whole. 

A. Cell-surface death receptors activate an extrinsic apoptotic pathway 

Procaspase activation can be initiated from outside the cell, as happens in the immune 

system when T cells kill their target cells by producing a signaling protein called 

Fas ligand. The Fas ligand binds to its receptor, Fas, on target cells. The cytoplasmic 

domain of a “death receptor” such as Fas is then triggered to bind adaptor proteins 

that link the receptor to procaspase-8 molecules. The aggregated procaspase-8 

molecules are thereby stimulated to cleave each other, initiating a proteolytic cascade 

that leads to apoptosis (Figure 19A). 

B. An intrinsic apoptotic pathway depends on mitochondria 

When cells are stressed (e.g., hypoxia), damaged (e.g., unrepaired DNA damage), or 

become abnormal in other ways, they can activate apoptosis from inside the cell by 

triggering a similar process of procaspase aggregation and activation. In response to 

stress or damage, pro-apoptotic signals induce mitochondria to release cytochrome 

c into the cytosol, where it binds and activates an adaptor protein called Apaf-1. This 

causes Apaf-1 to aggregate into a wheel-like complex called an apoptosome. This 

aggregate then recruits a set of procaspase-9 molecules, which become activated to 

trigger a caspase cascade causing cell death (Figure 19B). 

49


Apoptosis 

Figure 18. Programmed cell death. Fas During ligand development of limb, tissue present 

Fas 

between the digits is removed by apoptosis. 

Apoptosis 

Killer T-cell 

Target Cell 

Figure 19. Induction of apoptosis by either extracellular or intracellular signals. (A) Extracellular 

activation. Adaptor proteins bind the intracellular region of aggregated Fas proteins, causing the 

aggregation of procaspase-8 molecules. These then cleave one another to initiate the caspase cascade. (B) 

Intracellular activation. Mitochondria release cytochrome c, which binds to and causes the aggregation of 

the adaptor protein Apaf-1. Apaf-1 binds and aggregates procaspase-9 molecules, which are activated to 

trigger a caspase cascade, leading to apoptotic cell death (From Alberts et al., Molecular Biology of the 

Cell, 2002) 

50


Domains BH 1, 2, 3 BH 1, 2, 3, 4 BH 3 only 

Function Pro-apoptotic Anti-apoptotic Pro-apoptotic 

Examples Bak, Bax Bcl-2 Bad, Bid, Puma 

Table 2. Three subclasses of proteins in the Bcl-2 family that control apoptosis by the 

intracellular (intrinsic) pathway. 

The release of cytochrome c from the mitochondria is tightly controlled by members 

of the Bcl-2 family of proteins, all of which contain at least one BH protein domain. 

Within this family of proteins, there are three sub-classes (Table 2): two subclasses 

promote apoptosis (the “pro-apoptotic” BH123 proteins, which contain 3 different 

BH protein domains, and the BH3-only proteins), and one subclass antagonizes 

apoptosis (the “anti-apoptotic” Bcl-2 proteins). The BH3 domain is the only domain 

shared by all three subclasses of proteins, and it can mediate a direct binding 

interaction between one pro-apoptotic protein and one anti-apoptotic protein to form 

heterodimers. The central players are the BH123 family members, Bak and Bax, 

which can form channels in the mitochondrial outer membrane that cause cytochrome 

c and other proteins in the mitochondrion’s intermembrane space to be released into 

the cytoplasm, thereby activating procaspase-9 via Apaf-1. The anti-apoptotic Bcl-2 

proteins appear to bind directly to Bak and Bax to inhibit them, thereby serving to 

keep the cell alive. The remaining BH3-only pro-apoptotic subclass is composed 

of a large number of proteins that bind to various subsets of the anti-apoptotic 

Bcl-2 proteins, forming heterodimers with them. If large enough amounts of the 

BH3 proteins are present in the right combinations, they will dissociate all of these 

inhibitors from Bak and Bax, thereby permitting the channel formation and inducing 

cell death (Figure 20). 

In summary, it is the balance between the activities of the set of anti-apoptotic Bcl-2 

proteins and the two subclasses of pro-apoptotic proteins that determines whether 

a mammalian cell lives or dies by the intrinsic pathway of apoptosis. This balance 

is determined through a complex and poorly understood signaling network that 

continually monitors the state of the cell. For example, only if a cell is in its expected 

location in the organism will it receive the specific survival signals that it requires to 

prevent apoptosis. Thus it is not surprising that cancer cells often acquire mutations 

that allow them to alter the balance between pro- and anti-apoptotic proteins, making 

it less likely for them to commit suicide even under conditions when normal cells 

would. 

VI. 

p53, THE CELL CYCLE, and APOPTOSIS 

The cell cycle is controlled at certain stages by checkpoints. These are biochemical 

mechanisms that stop the cell cycle if certain conditions are not met. 

One checkpoint is the G1 DNA damage checkpoint. If cells contain unrepaired damage to 

their DNA, the cell cycle is arrested in G1. This arrest requires a key transcription factor, 

p53, which is activated by DNA damage (Figure 21). There are three components to the 

system: 1) a DNA damage sensor, 2) the Mdm2 protein that normally causes p53 to be 

degraded, and 3) the p53 protein itself. DNA damage causes phosphorylation of p53 and 

blocks the binding of Mdm2. This leads to the stabilization and accumulation of p53. p53 

can then bind to the promoter of the p21 Cdk inhibitor described earlier and activate its 

transcription, causing p21 to accumulate. The resulting inhibition of Cdks leads to cell 

cycle arrest. 

51


Figure 20. How pro-apoptotic BH3- 

only and anti-apoptotic Bcl2 proteins 

regulate the intrinsic pathway of 

apoptosis. (A) In the absence of an 

apoptotic stimulus, anti-apoptotic 

Bcl2 proteins bind to and inhibit the 

BH123 proteins on the mitochondrial 

outer membrane (and in the cytosol - 

not shown). (B) In the presence of an 

apoptotic stimulus, BH3-only proteins are 

activated and bind to the anti-apoptotic 

Bcl2 proteins so that they can no longer 

inhibit the BH123 proteins, which no 

become activated an aggregate in the 

outer mitochondrial membrane and 

promote the release of intermembrane 

mitochondrial proteins into the cytosol. 

Some activated BH3-only proteins may 

stimulate mitochondrial protein release 

more directly by binding to and activating 

the BH123 proteins. Although not shown, 

the anti-apoptotic Bcl2 protins are bound 

to the mitochondrial surface. (Reproduced 

with permission from Alberts et al. 

Molecular Biology of the Cell. Garland 

Publishing, 2008. Figure e18-11, p. 1124.) 

If p53 activation continues for a prolonged period of time, apoptosis ensues. This 

process kills cells with damaged DNA that remain unrepaired, and serves to remove cells 

from tissues that may otherwise accumulate mutations that would be passed on to their 

daughter cells. High levels of p53 are thought to activate apoptosis by increasing the 

transcription of several genes. One target gene is the BH123 protein Bax, whose gene is 

directly activated by p53 (Figure 22). 

In light of the important role p53 plays in preventing unrepaired DNA damage to be 

passed on to daughter cells, it is not surprising that p53 is found to play a central role in 

cancer development. In fact, the p53 pathway is mutated in nearly all cancers, thereby 

allowing damaged DNA to remain in cells as they proliferate (more in the lecture on 

Tumor Suppressor Genes and Oncogenes). 

52


Figure 21. How DNA damage 

activates p53 and causes cellcycle 

arrest. DNA damage 

activates a protein kinase that 

phosphorylates p53, preventing 

its degradation. This leads to the 

production of high levels of the 

Cdk inhibitor p21. (reproduced 

with permission from Alberts et 

al. Molecular Biology of the cell. 

5th Edition, Garland Publishing, 

2008: Fig 17-63.) 

Prolonged 

p53 

Activation 

p53 

promoter 

BAX gene 

Figure 22. DNA damage can lead to 

apoptosis. Prolonged activation of p53 in 

response to DNA damage results in apoptosis. 

p53 activates the transcription of 

several genes involved in apoptosis including 

that for the pro-apoptotic BH123 protein 

Bax shown here. 

cytochrome C 

apoptosis 

Bax channel 

53


VII. 

THE SPINDLE ASSEMBLY CHECKPOINT: THE IMPORTANCE OF 

REGULATED PROTEOLYSIS IN THE CELL 

In addition to monitoring the state of DNA in G1 before entering S phase, cells also 

monitor the state of the cell at several other checkpoints. One, called spindle assembly 

checkpoint, ensures that mitosis does not proceed beyond metaphase until the spindle is 

properly assembled. This checkpoint monitors the attachment of spindle microtubules 

to each kinetochore through the action of the Mad2 protein (Figure 23). There are two 

key features of the checkpoint: 1) Mad2 associates with kinetochores only when they 

are not attached to microtubules, and 2) Mad2 becomes activated for arresting mitosis 

only when bound to such kinetochores. If even one of the 46 human chromosomes 

is not attached correctly to microtubules, enough Mad2 is activated to keep the cell 

in metaphase. Only when the spindle has been properly assembled with all of the 

kinetochores bound to microtubules does Mad2 becomes inactive and allow anaphase to 

proceed. If there is a problem with spindle assembly, Mad2 will arrest the cell cycle until 

the problem is resolved. 

Active Mad2 exerts its effects by blocking the key regulator of the metaphase-toanaphase 

transition, the anaphase-promoting complex/cyclosome (APC/C). The APC/C 

is a member of a large family of important enzymes, called ubiquitin ligases, that trigger 

the regulated destruction of target proteins in the cell. The actual proteolysis is carried out 

by proteasomes, large protein complexes that pump selective proteins into their interior 

in order to cleave them into small fragments. 

As a ubiquitin ligase, the APC/C marks proteins for uptake into proteasomes by 

covalently adding multiple copies of the small protein called ubiquitin to them. The 

polyubiquitin chain added to a protein is recognized by the proteasome, causing the 

protein to be destroyed. One of the destroyed proteins is an inhibitor of the protein that 

centrosome 

microtubules 

Mad2 

cell cycle arrest 

kinetochore 

Mad2 

inactive 

Sister 

Chromatids 

Figure 23. Spindle assembly checkpoint. This checkpoint functions through the action of the Mad2 

protein, which binds to kinetochores that have not attached to microtubules. When bound to kinetochores, 

Mad2 triggers cell cycle arrest. Once microtubules are attached to all of the kinetichores, Mad2 is no 

longer active and the cell cycle proceeds. 

54


cuts the linkages holding the sister chromatid pairs together. The removal of the inhibitor 

allows the separation of sisters and unleashes anaphase. The S- and M-cyclins are the 

second major targets of the APC/C. The destruction of these cyclins inactivates the 

corresponding Cdks (see Figure 8). As a result, the many proteins phosphorylated by 

Cdks from S phase to early mitosis are dephosphorylated by various protein phosphatases 

that are present in the anaphase cell. This dephosphorylation of Cdk targets is required 

for the completion of M phase, including the final steps in mitosis and the process of 

cytokinesis. Not surprisingly, cells defective in the spindle assembly checkpoint show 

high rates of aneuploidy because of errors in chromosome segregation during mitosis. 

Defects in the spindle-assembly checkpoint, and specifically in Mad2, have been 

associated with tumorigenesis. 

VIII. 

THE EVOLUTION OF CELL SIGNALING AND CANCER 

Now that we have explored the key aspects of normal cell proliferation, we can begin 

to consider what goes awry in cancer cells. The following section considers theoretical 

aspects of the evolution of cell signaling and cancer to provide you with context for 

thinking about cancer development and treatment. (From Dr. Bruce Alberts) 

A. Elaborate cell signaling mechanisms had to evolve in multicellular organisms to 

prevent cancer. Various types of evidence suggest that single-celled life was present on 

the earth 3.5 billion years ago, about a billion years after the earth formed (prokaryotic 

cells such as bacteria). However, it appears to have required another two billion years 

to evolve the first multicellular organisms. Initially these were very small aggregates of 

eukaryotic cells that had learned how to cooperate, with each cell restraining its own 

growth for the good of the entire aggregate. Although this had the advantage of allowing 

each type of cell to specialize, it meant that each cell had to send and receive an elaborate 

set of signals to determine its appropriate behavior, and that fail-safe controls had to 

evolve to prevent the type of selfish cell behavior that we call cancer. 

As larger and larger organisms evolved, major improvements to these fail-safe controls 

had to develop in the form of multiple, largely redundant systems that prevent aberrant 

cell proliferation. Why Even with the overlapping set of proofreading mechanisms that 

allow us to replicate the three billion (3 x 10 9 ) nucleotide pairs in the human genome with 

an error rate of only about one in a billion (10 -9 ), the fact that humans are formed from 

about 10 14 cells means that billions of cells experience mutations every day, potentially 

disrupting the normal controls on cell growth. Viewed from this perspective, the 

surprising thing about large multicellular organisms is how infrequently cells misbehave 

to create a tumor. As we shall see, the reason we do not all die of cancer is that, in 

general, many different mutations need to accumulate in a single line of cells to cause 

this disease – perhaps 10 to 20. Obtaining a better understanding the multiple layers of 

control that are circumvented during tumorigenesis will be key to controlling cancer. 

Unfortunately, there is still much to learn in this critical area of research. 

B. Cells integrate the many signals that they receive in deciding whether to survive, 

grow and divide (proliferate), differentiate, or die (apoptosis). Every cell contains 

many different cell surface receptor molecules, each of which recognizes a particular 

molecule at the cell exterior. Some of these bind to signaling molecules that have been 

secreted by neighboring cells, others bind to protein molecules held in the plasma 

membrane of tightly opposed adjacent cells, while others bind to the extracellular matrix. 

All of these signal molecules work in combinations to regulate the behavior of the cell, 

55


with each of the hundreds or thousands of different cell types in our bodies responding 

to this babble of signals differently. As shown in Figure 24, an individual cell generally 

requires multiple signals just to survive. It requires additional signals to grow and divide, 

and a different set of additional signals to differentiate. If deprived of its required survival 

signals, a cell will undergo cell suicide (apoptosis). The actual situation is even more 

complex than illustrated in Figure 24, since some extracellular signal molecules act to 

inhibit these and other cell behaviors, or even to induce apoptosis. 

How exactly a cell makes each of the all-or-none decisions illustrated in Figure 24 is 

not understood in detail. Speaking metaphorically, the decision is analogous to “cell 

thinking”. Cells integrate the many signals they receive through a “cross-talk” between 

different intracellular events triggered by different cell surface receptors. Some of the 

cross talk depends on simple “coincidence detectors”, as in the example shown in Figure 

25. Here two different signaling events are needed to activate a single protein inside the 

cell, because the protein needs to be phosphorylated at two different sites to become 

active. Thus, the activation of this protein occurs if, and only if, two specific extracellular 

signals are present simultaneously. But much of the cross talk is more complex and not 

yet decipherable. 

Figure 24. How an animal cell depends on multiple extracellular signal molecules. 

Reproduced with permission from Alberts et al. Molecular Biology of the Cell. Garland 

Publishing, 2008. 

56


Figure 25. Signal integration inside the cell. Here signals A and B each trigger a different intracellular 

signaling pathway. Both pathways involve the activation of a protein kinase that phosphorylates protein 

Y, but at a different site. Because both sites must be phosphorylated for protein Y to become activated, 

protein Y serves as a coincidence detector that indicates that both extracellular molecules A and B 

are present. (Reproduced with permission from Alberts et al. Molecular Biology of the Cell. Garland 

Publishing, 2008.) 

Why is it so important to understand how cells “think” Cancer can be viewed as a 

disease in which a cell has accumulated so many changes in its intracellular processes 

that it has escaped from all of its normal requirements, thinking that it should proliferate 

and survive independent of its environment. The ideal cancer therapy would be based 

on an understanding of the exact, highly abnormal intracellular state of the cells in 

a particular tumor. One might then be able to induce apoptosis in the cancer cells by 

exposing them to a mixture of two or three specific signaling molecules (or inhibitors 

of such molecules), with no deleterious effect on normal cells. It is important to keep 

in mind, however, that each tumor has its own unique set of mutations and aberrant 

signaling pathways, resulting from a long evolutionary process of random mutation and 

natural selection during tumor progression. Thus, we should view cancer as a collection 

of different but related diseases, each of which may require its own specific combination 

of therapies to treat it. 

Acknowledgements: 

Significant contributions to this lecture were made by 

Hiten Madhani, PhD, Department of Biochemistry and Biophysics, who originally 

developed this lecture (lecturer 2002 – 2006); and 

Bruce Alberts, PhD, Department of Biochemistry and Biophysics (lecturer 2007). 

57


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