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 />
in multiple ways by the accumulation <strong>of</strong> the cyclin,<br />
at the level <strong>of</strong> assembly into the cyclin/CDK<br />
complexes, <strong>and</strong> by specific phosphorylation <strong>and</strong><br />
dephosphorylation <strong>of</strong> the components. One<br />
additional <strong>and</strong> important regulatory mechanism<br />
<strong>of</strong> these G 1<br />
cyclin/CDK complexes is their<br />
association with CKIs. The CKIs either physically<br />
bind <strong>and</strong> block the cyclin/CDK complexes or<br />
inhibit substrate/ATP access. Early investigators<br />
postulated that some <strong>of</strong> these CKIs have additional<br />
functions (6). CKIs are grouped to two gene<br />
families: the smaller INK4 (inhibitors <strong>of</strong> CDK4)<br />
<strong>and</strong> the larger CIP/KIP (CDK interacting protein/<br />
kinase inhibitory protein).<br />
The INK4 family is composed <strong>of</strong><br />
p16INK4A, p15INK4B, p18INK4C, p19INK4D<br />
(7). The common structural feature among them<br />
is the ankyrin repeats <strong>and</strong> all <strong>of</strong> them can inhibit<br />
CDK4. They compete with D-type cyclins for<br />
binding to the CDK subunit (8). The INK4 family<br />
proteins are characterized by specific binding to<br />
CDK4 <strong>and</strong> CDK6. Tissue-specific functions <strong>of</strong><br />
this family <strong>of</strong> cell cycle inhibitors have been<br />
suggested recently because <strong>of</strong> the diversity in the<br />
pattern <strong>of</strong> expression <strong>of</strong> INK4 genes (9). The<br />
INK4 proteins are commonly lost or inactivated<br />
by mutations in many different cancer types. In<br />
addition to their role in arresting cells in the G 1<br />
-<br />
phase <strong>of</strong> the cell cycle, it also increases interests<br />
<strong>of</strong> researchers that they have been shown to<br />
participate in different cellular processes other<br />
than cell cycle regulation. The discoveries <strong>of</strong><br />
involvement <strong>of</strong> INK4 proteins include their<br />
functions in senescence, apoptosis, DNA repair,<br />
<strong>and</strong> multistep oncogenesis. The p16INK4A is a<br />
tumor suppressor that inhibits the cyclin D-<br />
associated kinase complexes. Loss <strong>of</strong> function in<br />
p16INK4A results in the same effect <strong>of</strong> loss <strong>of</strong><br />
function in Rb (10). It has been reported that<br />
p14ARF protein is closely related to p16INK4A.<br />
The ARF protein, a spliced variant <strong>of</strong> the INK4A<br />
gene, is known to have a function <strong>of</strong> stabilizing<br />
p53 by preventing degradation (11). The second<br />
129<br />
INK4 family protein, p15INK4B, regulates the<br />
cell cycle clock by inhibiting cyclinD/CDK4- or<br />
cyclinD/CDK6-mediated phosphorylation <strong>of</strong> Rb.<br />
Induction <strong>of</strong> p15INK4B-triggered G 1<br />
-phase arrest<br />
occurs in response to TGF-â (12). Loss <strong>of</strong><br />
p15INK4B gene is associated with lymphoproliferative<br />
disorders <strong>and</strong> tumor formation (13).<br />
The p15INK4B mediated pathways that control<br />
G 1<br />
/S transition are frequently deregulated in<br />
human cancers such as prostate cancer,<br />
melanoma, pituitary adenoma, acute myeloid<br />
leukemia, gastric cancer. The p18INK4C seems<br />
to play an important role in growth control <strong>and</strong> its<br />
expression is found in many different tissue types.<br />
It has been suggested that loss <strong>of</strong> p18INK4C<br />
function results in shortening the G 1<br />
phase <strong>and</strong><br />
thus facilitates the cell cycle progression.<br />
Interestingly, functional synergism between<br />
p18INK4C <strong>and</strong> p27KIP1 has been implicated in<br />
pituitary tumors (14, 15). A recent study <strong>of</strong> the<br />
gene encoding p19INK4D is induced by vitamin<br />
D3 derivatives <strong>and</strong> by retinoids. Therefore, the<br />
chemopreventive effects <strong>of</strong> vitamin D3 may be<br />
associated with this induction <strong>of</strong> p19INK4D<br />
expression. Recent studies reported that the<br />
knockdown <strong>of</strong> p19INK4D renders cells sensitive<br />
to autophagic cell death (16)<br />
The second group <strong>of</strong> cell cycle inhibitors<br />
is CIP/KIP family proteins: p21CIP1, p27KIP1<br />
<strong>and</strong> p57KIP2. The structural feature <strong>of</strong> these<br />
proteins shows an ability to bind a whole cyclin/<br />
CDK complex, different from INK4 family<br />
proteins’ ability to bind CDK protein alone by<br />
competing for cyclin’s binding. They can function<br />
throughout the all cell cycle phases by interacting<br />
with different kinds <strong>of</strong> cyclin D, E, A/CDK<br />
complexes. Although initially identified as cell cycle<br />
inhibitors, these CIP/KIP family proteins have<br />
emerged to display roles in different cellular<br />
functions ranging from apoptosis to cell migration<br />
<strong>and</strong> have appeared to add their lists on other<br />
important cellular functions. These functions are<br />
essential for the maintenance <strong>of</strong> normal cell<br />
Jinhwa