April Journal-2009.p65 - Association of Biotechnology and Pharmacy

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Current Trends in Biotechnology and Pharmacy Vol. 3 (2) 128-137, April 2009. ISSN 0973-8916 Regulation of CIP/KIP cell cycle inhibitors and their biological implications 128 Jinhwa Lee Dept. of Clinical Lab Science, Dongseo University, Busan 617-716, Korea For correspondence: jinhwa2000@gdsu.dongseo.ac.kr Abstract The cell cycle regulation is a key homeostatic device upon the cellular decision during the multi processes like proliferation, differentiation, survival and death. Human cancers can arise from the result of functional failure in cell cycle regulators. Therefore, activity of the major cell cycle regulator, cyclin-dependent kinase (CDK), is tightly regulated by cyclin dependent kinase inhibitors (CKIs) such as the p21CIP1 and p27KIP1. These CKIs, mainly functioning as a cyclinE/CDK2 complex inhibitor during the G 1 cell cycle, have been reported to play disparate roles including the assembly of cyclinD/CDK4,6 and others that apparently assist cell growth if not help carcinogenesis. While their genetic disruptions are rarely found in human cancers, low expression levels or cytoplasmic mislocalizations of the p21CIP1 and p27KIP1 often correlate with human malignancies. Recent studies show that signalling kinases can directly phosphorylate these proteins as a substrate and change their activities in the role of a cell cycle inhibitor by switching interacting partner proteins after the phosphorylation-driven structural modifications. This report will discuss the complex regulatory mechanisms of p21CIP1 and p27KIP1 proteins on the cue of extracellular signals and their indications of functional importance to carcinogenesis. Keywords: Cell cycle; Proliferation; CDK, p21CIP1, p27KIP1 Introduction The mammalian cell cycle operates with four distinct phases, G 1 , S, G 2 and M in a tightly regulated manner, each of which should be completed before the next begins (1). Progression of cell cycle transitions is mediated by sequential activation of the cyclin/CDK complexes. Since timely regulation is absolutely important in normal cell cycle progression, cyclin/CDK complexes are integrators of the multiple signals. Those signals include extracellular signals such as cytokines, hormones, or physical interactions with extracellular matrix or other cells. In mammalian tissues, several cyclin/CDK complexes play a role in the G 1 -to-S transition (2). In early G 1 , D-type cyclins are elevated from mitogenic signals and activate CDK4 or CDK6 (3). The three D-type cyclins (D1, D2 and D3) are expressed differentially when CDK4 and CDK6 are coexpressed in many cell types (4). In late G 1 , cyclin E/CDK2 activity is elevated due to the initial cyclin D/CDK4,6 activation, not by mitogenic stimulation. The increased cyclin E/CDK2 activity phosphorylates pRb and releases E2F transcription factors from an inactive or repressive pRb–E2F complex, which initiates a whole new synthesis of proteins involved in DNA replication (5). The E2F genes also involve some protooncogenes and some cell-cycle regulatory proteins, as well as cyclin E that forms a feedback loop to expedite and commit to enter S phase. Activity of cyclin/CDK complexes is regulated Regulation of CDK inhibitors
Current Trends in Biotechnology and Pharmacy Vol. 3 (2) 128-137, April 2009. ISSN 0973-8916 in multiple ways by the accumulation of the cyclin, at the level of assembly into the cyclin/CDK complexes, and by specific phosphorylation and dephosphorylation of the components. One additional and important regulatory mechanism of these G 1 cyclin/CDK complexes is their association with CKIs. The CKIs either physically bind and block the cyclin/CDK complexes or inhibit substrate/ATP access. Early investigators postulated that some of these CKIs have additional functions (6). CKIs are grouped to two gene families: the smaller INK4 (inhibitors of CDK4) and the larger CIP/KIP (CDK interacting protein/ kinase inhibitory protein). The INK4 family is composed of p16INK4A, p15INK4B, p18INK4C, p19INK4D (7). The common structural feature among them is the ankyrin repeats and all of them can inhibit CDK4. They compete with D-type cyclins for binding to the CDK subunit (8). The INK4 family proteins are characterized by specific binding to CDK4 and CDK6. Tissue-specific functions of this family of cell cycle inhibitors have been suggested recently because of the diversity in the pattern of expression of INK4 genes (9). The INK4 proteins are commonly lost or inactivated by mutations in many different cancer types. In addition to their role in arresting cells in the G 1 - phase of the cell cycle, it also increases interests of researchers that they have been shown to participate in different cellular processes other than cell cycle regulation. The discoveries of involvement of INK4 proteins include their functions in senescence, apoptosis, DNA repair, and multistep oncogenesis. The p16INK4A is a tumor suppressor that inhibits the cyclin D- associated kinase complexes. Loss of function in p16INK4A results in the same effect of loss of function in Rb (10). It has been reported that p14ARF protein is closely related to p16INK4A. The ARF protein, a spliced variant of the INK4A gene, is known to have a function of stabilizing p53 by preventing degradation (11). The second 129 INK4 family protein, p15INK4B, regulates the cell cycle clock by inhibiting cyclinD/CDK4- or cyclinD/CDK6-mediated phosphorylation of Rb. Induction of p15INK4B-triggered G 1 -phase arrest occurs in response to TGF-â (12). Loss of p15INK4B gene is associated with lymphoproliferative disorders and tumor formation (13). The p15INK4B mediated pathways that control G 1 /S transition are frequently deregulated in human cancers such as prostate cancer, melanoma, pituitary adenoma, acute myeloid leukemia, gastric cancer. The p18INK4C seems to play an important role in growth control and its expression is found in many different tissue types. It has been suggested that loss of p18INK4C function results in shortening the G 1 phase and thus facilitates the cell cycle progression. Interestingly, functional synergism between p18INK4C and p27KIP1 has been implicated in pituitary tumors (14, 15). A recent study of the gene encoding p19INK4D is induced by vitamin D3 derivatives and by retinoids. Therefore, the chemopreventive effects of vitamin D3 may be associated with this induction of p19INK4D expression. Recent studies reported that the knockdown of p19INK4D renders cells sensitive to autophagic cell death (16) The second group of cell cycle inhibitors is CIP/KIP family proteins: p21CIP1, p27KIP1 and p57KIP2. The structural feature of these proteins shows an ability to bind a whole cyclin/ CDK complex, different from INK4 family proteins’ ability to bind CDK protein alone by competing for cyclin’s binding. They can function throughout the all cell cycle phases by interacting with different kinds of cyclin D, E, A/CDK complexes. Although initially identified as cell cycle inhibitors, these CIP/KIP family proteins have emerged to display roles in different cellular functions ranging from apoptosis to cell migration and have appeared to add their lists on other important cellular functions. These functions are essential for the maintenance of normal cell Jinhwa
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April Journal-2009.p65 - Association of Biotechnology and Pharmacy

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