The p16 protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that decelerates the cell cycle by inactivating the CDKs that phosphorylate retinoblastoma protein (Rb).
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The protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that slows down the progression of the cell cycle by inactivating the Cyclin dependent kinase that phosphorylates the retinoblastoma protein (pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53. Cyclin D1 promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase to S phase is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase or enter into the S phase, where cells are destined to divide. when cells enter in to the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1 is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis. When Cyclin D1 interacts with cyclin-dependent kinase-4 or 6 (CDK-4/6), it leads to a conformational change to CDK-4 or 6 however, cyclin D1 does not undergo conformational change. The interaction of cyclin D and CDK4 forms a complex that inactivates the tumor suppressor protein retinoblastoma through phosphorylation. Phosphorylation of pRb releases transcription factors such as E2Fs which then activate a series of events that allow entry into the S-phase and promotes cell division. However, Phosphorylation of pRb leads to a conformational change to E2F as well. However,protein p15 and protein p16 are inhibit cyclin D1 from binding to the CDKs. Another important Protein tumor suppressor is p21 and what it does is block the CDKs at any point in the cell cycle. Protein p21 is under control of p53 tumor suppressor protein. Some of the biological functions of protein p53 are as a transcriptional factor and also it regulates apoptosis. The stochometric level of protein p53 in the cell is very small because if it is large then it kills the cells. P53 is regulated by MDM2 which regulates the amount of protein or in other words it facilitates degradation in DNA damage checkpoint. Oncogenic ras can transform most immortal cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Researches show that expression of oncogenic ras in primary human cells results in a permanent G1 arrest and this arrest is by ras and is accompanied by accumulation of p53 and p16. However, inactivation of either p53 or p16 prevents ras-induced arrest in cells. This suggests that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. It is believed that negation of ras-induced senescence may be relevant during multistep tumorigenesis.
For clinical significances, expression of cyclin D1/p16/pRb play a critical role in tumorigenesis. However, when protein p16 is overexpression it leads to cervical cancer because of the functional inactivation of pRb by human papillomavirus E7 protein. In the case of cervical cancer PRB is functionally inactivated by HPV oncoproteins and that results in p16 overexpression. In addition to that, overexpression of the protein p16 is a useful diagnostic tool for cervical cancer laboratory screening. Many recent and previous immunohistochemical studies have clearly demonstrated that p16 is strongly expressed in almost all cervical cancers. Many people mistakenly take the fact that the low expression of protein p16 in the cell as a free condition of cervical cancer however it is not always true. Protein p16 regulates cell proliferation and pRb acts as a negative regulator of protein p16. It was also shown that p16 is involved in the regulation of the cellular life span and accumulates in senescent cells. Some studies also reported that transcriptional silencing of the p16 promoter by hypermethylation as a dominant mechanism of inactivation of the tumor suppressor in head and neck squamous cell carcinoma. It is believed that excesse of cyclin D and cyclin E is produced in breast cancer cells. A possible therapy in cancer is to by blocking cyclins and CDK’s activates. the only possible way of inactivating the CDKs is through the inhibitor protein p16. In the p16/cyclin D1/cdk4/pRb cell cycle regulatory cascade, the correlation between pRb and p16 is believed to be obvious in various cancer types. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 cell cycle progression, and may represent a common pathway to tumorigenesis.
Protein p16 pathway mechanism in cell cycle begins when cyclin D which is a kinase activator binds itself to CDK4/ CDK6. upon the interaction CDK undergoes conformational change and the complex formed triggers pRB phosphorylation. then, pRB which undergoes conformational change and is now functionally inactivated since its size, shape and charge is different hence it can not fit as before. However, the phosphorylated pRB releases a transcription factor E2F that causes induction of p16 expression. Then, pl6 proceeds to bind all CDK4/CDK6 hence, cyclin D is no longer protected by association with its CDK4/CDK6 partner.p16 appears in many pathway mechanisms including DNA damage checkpoint, G1/S checkpoint and many others.
p16 has been shown to interact with
