April Journal-2009.p65 - Association of Biotechnology and Pharmacy
April Journal-2009.p65 - Association of Biotechnology and Pharmacy
April Journal-2009.p65 - Association of Biotechnology and Pharmacy
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Current Trends in <strong>Biotechnology</strong> <strong>and</strong> <strong>Pharmacy</strong><br />
Vol. 3 (2) 128-137, <strong>April</strong> 2009. ISSN 0973-8916<br />
p27KIP1 by ERK1 is a signal for ubiquitination<br />
<strong>and</strong> phosphorylation on more than one threonine<br />
sites by different kinases involves cytoplasmic<br />
localization. CyclinE/CDK2 phosphorylates<br />
p27KIP1 on Thr187 <strong>and</strong> leads to ubiquitindependent<br />
phosphorylation. p27KIP1 protein<br />
phosphorylated by AKT at Thr157 <strong>and</strong> Thr198<br />
becomes better assembler <strong>of</strong> cyclin D/CDK4<br />
complex formation (32, 33). Since p27KIP1<br />
binding to cyclin D/CDK4 facilitates activation<br />
<strong>of</strong> cyclinE/CDK2 through sequestration <strong>of</strong> the<br />
inhibitory protein, the differential binding <strong>of</strong><br />
p27KIP1 to the distinct CDKs during G 1<br />
cell cycle<br />
can be attributed to the phosphorylation status <strong>of</strong><br />
p27KIP1. Altered p27KIP1 phosphorylation<br />
would then switch p27KIP1 cyclin/complexes. As<br />
p27KIP1 phosphorylation is cell cycle dependent,<br />
the cyclinE/CDK2 inhibitory activity <strong>of</strong> p27KIP1<br />
is maximal in G 0<br />
<strong>and</strong> falls as cells move through<br />
G 1<br />
into S phase. At the same time, the cyclin D/<br />
CDK4 bound p27KIP1 is maximal during early<br />
G 1<br />
. Anti-mitogenic signaling dissociates p27KIP1<br />
from CDK4/6 complexes <strong>and</strong> accumulates in<br />
cyclinE/CDK2. As with Thr145 phosphorylation<br />
<strong>of</strong> p21CIP1 by PIM1, PIM kinases promote cell<br />
cycle progression by phosphorylating <strong>and</strong> downregulating<br />
p27KIP1<br />
Phosphorylation affects degradation <strong>and</strong><br />
localization <strong>of</strong> p21CIP1 <strong>and</strong> p27KIP1<br />
proteins<br />
Mitogenic signalings <strong>of</strong>ten cause downregulation<br />
through accelerated proteolysis <strong>and</strong><br />
mislocalization out <strong>of</strong> nucleus into cytoplasm <strong>of</strong><br />
p21CIP1 <strong>and</strong> p27KIP1 proteins. The fact that<br />
mutation or deletion <strong>of</strong> p21CIP1 <strong>and</strong> p27KIP1<br />
genes is uncommon in human cancers suggests<br />
that post-transcriptional regulatory mechanisms<br />
may be more important in the process <strong>of</strong> cancer<br />
development. These proteins are short lived <strong>and</strong><br />
their expression is tightly regulated by<br />
proteasome-mediated protein degradation. The<br />
ubiquitination-dependent degradation pathway<br />
133<br />
involves E3-ubiquitin ligases, such as SCFSKP2<br />
(34). While less <strong>of</strong>ten than accelerated proteolysis<br />
in human cancers, cytoplasmic localization <strong>of</strong><br />
p27KIP1 – that <strong>of</strong> p21CIP1 in cancers is less<br />
understood- has been observed in some advanced<br />
cancers. Many tumor suppressor proteins<br />
including p53, FOXO family gene products,<br />
p21CIP1 <strong>and</strong> p27KIP1 proteins function when<br />
they are present in the cell to prevent cancer<br />
initiation or progression. Inhibition <strong>of</strong> FOXO family<br />
proteins that compose p21CIP1 <strong>and</strong> p27KIP1 gene<br />
transcription factors can result in the negative<br />
transcriptional regulation <strong>of</strong> p21CIP1 <strong>and</strong><br />
p27KIP1 proteins. Therefore, mislocalization <strong>of</strong><br />
those nuclear proteins including FOXO family<br />
proteins into the cytoplasm can disable them as a<br />
tumor suppressor. In the cytoplasm, FOXO family<br />
proteins can no longer exercise a transcription<br />
factor, nor do the p21CIP1 <strong>and</strong> p27KIP1 proteins<br />
the cyclinE/CDK2 inhibitor. Export <strong>of</strong> nuclear<br />
proteins generally involves modification in the<br />
leucine-rich nuclear export signal sequences<br />
which allows binding to the CRM1/RanGTP<br />
proteins <strong>and</strong> then the nuclear proteins are ready<br />
for the journey out <strong>of</strong> nucleus to the cytoplasm.<br />
SCFSKP2 <strong>and</strong> CRM1 proteins are notably<br />
recognized in the study <strong>of</strong> cancer development<br />
for this very reason that they help nuclear tumor<br />
suppressive proteins evacuate from the functional<br />
site, nucleus.<br />
The p21CIP1 protein level is mainly<br />
controlled at the transcriptional level. Nonetheless,<br />
the fact that a half-life <strong>of</strong> p21CIP1 is less than 30<br />
min dictates p21CIP1 stability as a considerable<br />
control site. Cytoplasmic localization <strong>of</strong> this<br />
nuclear CDK inhibitor <strong>of</strong> the p21CIP1 protein can<br />
be added as another regulatory site. Modification<br />
<strong>of</strong> p21CIP1 by phosphorylation that changes<br />
interaction with other cellular proteins is one<br />
mechanism to control the protein level in general<br />
by qualifying the protein for ubiquitin-dependent<br />
proteosomal degradation <strong>and</strong> by mislocalization<br />
into cytoplasm. Degradation <strong>of</strong> p21CIP1 protein<br />
Jinhwa