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Working in mouse models, it was also shown that whilst mice lacking p21 were healthy, spontaneous tumours developed and G1 checkpoint control was compromised in cells derived from these mice. [27] [13] Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage.
The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. [5] [6] In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. [5] [6] The expression of PUMA is regulated by the tumor suppressor p53.
Chk1/2 phosphorylate cdc25 which, in addition to being inhibited, is also sequestered in the cytoplasm by the 14-3-3 proteins. 14-3-3 are upregulated by p53, which, as previously mentioned, is activated by Chk1 and ATM/ATR. p53 also transactivates p21, and both p21 and the 14-3-3 in turn inhibit cyclin B-cdc2 complexes through the ...
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial in vertebrates , where they prevent cancer formation. [ 5 ]
The p53 p63 p73 family is a family of tumor suppressor genes. [1] [2] This gene family codes the proteins: p53; TP73L (also known as "p63") p73; They are sometimes considered part of a "p53 family." When overexpressed, these proteins are known to be involved in tumor pathogenesis. [3]
The maintenance of such arrest in the G2 phase is further sustained by p53 and p21. In the absence of p53 or p21, it was demonstrated that radiated cells progressed into mitosis. [17] The absence of p21 or 14-3-3 cannot sufficiently inhibit the CyclinB-Cdc2 complex, thus exhibiting the regulatory control of p53 and p21 in the G2 checkpoint in ...
This degradation causes release of p21 from Cdk4 complexes, which inactivates Cdk2 in a p53-independent manner. Another way in which DNA damage targets Cdks is p53-dependent induction of p21, which inhibits cyclin E-Cdk2 complex. In healthy cells, wild-type p53 is quickly degraded by the proteasome.
Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression. [2]