Tumorigenic activity of p21Waf1/Cip1 in thymic lymphoma (original) (raw)
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Tumor susceptibility of p21(Waf1/Cip1)-defcient mice
Cancer Research
The cell cycle regulator p21 mediates the ability of the tumor suppressor p53 to arrest cellular proliferation. We have examined the involvement of p21 in tumor suppression by following a large cohort of p21-deficient mice for an extended period of time. We report that p21-deficient mice develop spontaneous tumors at an average age of 16 months, whereas wild-type mice are tumor-free beyond 2 years of age. The tumors arising in p21-null mice derive from a variety of cell types and include hematopoietic ( approximately 65% of the tumors), endothelial ( approximately 20%), and epithelial ( approximately 10%) tumors. We have also studied radiation-induced carcinogenesis to test whether, in this setting, p53 exerts its tumor suppressor activity mainly through apoptosis, rather than through p21-mediated cell-cycle arrest. Concurring with this, p21-deficient mice did not show increased susceptibility to radiation-induced carcinogenesis. On the contrary, they were protected relative to wild...
Tumor susceptibility of p21Waf1/Cip1-deficient mice
Cancer research, 2001
The cell cycle regulator p21 mediates the ability of the tumor suppressor p53 to arrest cellular proliferation. We have examined the involvement of p21 in tumor suppression by following a large cohort of p21-deficient mice for an extended period of time. We report that p21-...
Combined loss of p21waf1/cip1 and p27kip1 enhances tumorigenesis in mice
Laboratory Investigation, 2011
The cell cycle inhibitors p21 Waf1/Cip1 and p27 Kip1 are frequently downregulated in many human cancers, and correlate with a worse prognosis. We show here that combined deficiency in p21 and p27 proteins in mice is linked to more aggressive spontaneous tumorigenesis, resulting in a decreased lifespan. The most common tumors developed in p21p27 double-null mice were endocrine, with a higher incidence of pituitary adenomas, pheochromocytomas and thyroid adenomas. The combined absence of p21 and p27 proteins delays the incidence of radiation-induced thymic lymphomas with a higher apoptotic rate, measured by active caspase-3 and cleaved PARP-1 immunoexpresion. These results provide experimental evidence for a cooperation of both cyclin-dependent kinase inhibitors in tumorigenesis in mice.
Cancer Letters, 2002
p21 Waf1/Cip1/Sdi1 is best known as a broad-specificity inhibitor of cyclin/cyclin-dependent kinase complexes, but p21 also interacts with many other regulators of transcription or signal transduction. p21 induction, which is mediated by p53 and by p53-independent mechanisms, is essential for the onset of cell cycle arrest in damage response and cell senescence. The effects of p21 knockout in mice and its expression patterns in human cancer are consistent with a role for p21 as both a tumour suppressor and an oncogene. Several functions of p21 are likely to promote carcinogenesis and tumour progression. These include endoreduplication and abnormal mitosis that develop in tumour cells after release from p21-induced growth arrest, the ability of p21 to inhibit apoptosis through several different mechanisms, and its ability to stimulate transcription of secreted factors with mitogenic and anti-apoptotic activities. The latter effects of p21 show close resemblance to paracrine activities of senescent cells and to tumour-promoting functions of stromal fibroblasts. Therapeutic strategies targeting the oncogenic consequences of p21 expression may provide a new approach to chemoprevention and treatment of cancer.
Cell Reports, 2013
Activation of apoptosis through transcriptional induction of Puma and Noxa has long been considered to constitute the critical (if not sole) process by which p53 suppresses tumor development, although G1/S boundary cell-cycle arrest via induction of the CDK inhibitor p21 has also been thought to contribute. Recent analyses of mice bearing mutations that impair p53-mediated induction of select target genes have indicated that activation of apoptosis and G1/S cell-cycle arrest may, in fact, be dispensable for p53mediated tumor suppression. However, the expression of Puma, Noxa, and p21 was not abrogated in these mutants, only reduced; therefore, the possibility that the reduced levels of these critical effectors of p53-mediated apoptosis and G1/S-cell-cycle arrest sufficed to prevent tumorigenesis could not be excluded. To resolve this important issue, we have generated mice deficient for p21, Puma, and Noxa (p21 À/À puma À/À noxa À/À mice). Cells from these mice were deficient in their ability to undergo p53mediated apoptosis, G1/S cell-cycle arrest, and senescence. Nonetheless, these animals remained tumor free until at least 500 days, in contrast to p53-deficient mice, which had all succumbed to lymphoma or sarcoma by 250 days. Interestingly, DNA lesions induced by g-irradiation persisted longer in p53-deficient cells compared to wild-type or p21 À/À puma À/À noxa À/À cells, and the former failed to transcriptionally activate several p53 target genes implicated in DNA repair. These results demonstrate beyond a doubt that the induction of apoptosis, cell-cycle arrest, and possibly senescence is dispensable for p53-mediated suppression of spontaneous tumor development and indicate that coordination of genomic stability and possibly other processes, such as metabolic adaptation, may instead be critical. * This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
p21B, a variant of p21Waf1/Cip1, is induced by the p53 family
Oncogene, 2002
Alternative splicing or expression from an alternate promoter can produce variants of a gene. To determine whether the p21 Waf1/Cip1 locus is regulated by these mechanisms, we searched for and found two transcripts, p21B and p21C, that are expressed from an alternate promoter in the ®rst intron of the p21 gene. While p21C encodes the p21 cyclin-dependent kinase inhibitor, p21B encodes a novel protein and the transcript is ubiquitously expressed in 16 human tissues tested. Like p21, both p21B and p21C are induced by DNA damage, p53, and other p53 family members through a proximal p53 response element in the promoter of p21B and p21C. However, unlike p21, which induces cell cycle arrest, we found that overexpression of p21B induces apoptosis. These ®ndings indicate that the p21 locus expresses at least two structurally distinct, but functionally related, variants of the p21 gene from discrete promoters.
Cancer Gene Therapy, 2003
Expression of exogenous wild-type (wt) p53 protein can suppress the growth and/or induce apoptosis in different tumor cells. The effect of exogenous p21 WAF1/CIP1 expression is more controversial: while it can induce apoptosis in some cells, it can protect against p53-mediated apoptosis in others. We used adenoviral vectors to introduce p53 and p21 WAF1/CIP1 genes into human tumor cell lines with different p53 and/or p21 WAF1/CIP1 status. The cell growth inhibition and the induction of apoptosis were measured. Overexpression of wt p53 induced more efficient growth inhibition and apoptosis in SW 620 (mutant p53) and HeLa (inactivated p53 protein) than in MCF-7 (wt p53) and CaCo-2 cell line, which was the most resistant to p53 overexpression despite the p53 mutation. Unlike HeLa and SW 620 cells, the basal p21 protein level was readily detected in CaCo-2 and MCF-7 cells. Overexpression of p21 WAF1/CIP1 gene induced somewhat less pronounced growth inhibition of all cell lines tested, but it also induced apoptosis in HeLa and SW 620 cells. These results suggest that the basal, but not the inducible, levels of p21 WAF1/CIP1 protein in tumor cells could protect from p53-mediated apoptosis. On the other hand, overexpression of p21 WAF1/CIP1 gene itself can induce apoptosis in cells with no basal p21 WAF1/CIP1 protein level. Possible mechanisms of the differential response to these genes are discussed.