Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency

Abstract

Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells.To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2ΔBΔM in p21-/- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn-/-mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2ΔBΔM in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/-TRF2ΔBΔM, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/-TRF2ΔBΔM, loss of p21 function induced p53 mutation and tumorigenesis.To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc-/-Wrn-/-), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.

Quercetin has a protective effect on atherosclerosis via enhancement of autophagy in ApoE‑/‑ mice

“…As a transcription factor, P53 accumulates in senescent cells and directly leads to cell senescence (28). P21 is a negative regulator of the cell cycle, and serves a key role in cellular senescence (29). In the present study, an AS animal model was induced by feeding ApoE −/− mice a HFD for 12 weeks.…”

Telomere length and telomerase activity during folliculogenesis in mammals

“…As telomeres play important roles in many cellular events including meiosis, nuclear organization, and genomic integrity throughout the lifespan of eukaryotic cells, their dysfunctions associate with various types of diseases including Werner syndrome [84], dyskeratosis congenita [85], Bloom syndrome [86], Fanconi anemia [87], and cancer [88]. Furthermore, there is a close relationship between telomeres/telomerase activity and female infertility caused by ovarian aging [89], polycystic ovary syndrome (PCOS) [90], and premature ovarian failure (POF) [23].…”

The Distinct Function of p21Waf1/Cip1 With p16Ink4a in Modulating Aging Phenotypes of Werner Syndrome by Affecting Tissue Homeostasis

“…On the other hand, we also observed that some senescent WS MEFs could spontaneously mutate the Trp53 gene and thus diminished p21 function, and these cells were able to form ALT tumors in SCID mice. The exogenous expression of p21 in these cells rebuilt the senescence status ( Jia et al, 2012 ; Si et al, 2018 ). These data were consistent with previous findings and suggested that the p53 or p21 functional loss could also rescue cellular senescence, but with the price of tumorigenesis ( Ferbeyre and Lowe, 2002 ).…”

“…However, our data also showed that when we strengthened telomere dysfunction with Wrn deficiency and TRF2 ΔBΔM overexpression ( Wrn –/– TRF2 ΔBΔM ), p21 deficiency with this severe telomere dysfunction resulted in tumorigenesis. Our data suggest that p21 deficiency plays a distinct role in the response to different degrees of telomere dysfunction, reversing aging or tumorigenesis ( Si et al, 2018 ).…”