Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse

Abstract

The Rb/p16 Ink4a and p53/p19Arf tumor suppressor pathways have been linked to diverse cancer-relevant processes, including those governing the cellular responses to telomere dysfunction. In this study, we sought to provide direct genetic evidence of a role for the Ink4a/Arf tumor suppressor gene, encoding both p16 Ink4a and p19 Arf , in modulating the cellular and tissue phenotypes associated with telomere dysfunction by using the mTerc Ink4a/Arf mouse model. In contrast to the rescue associated with p53 deficiency, Ink4a/Arf deficiency did not attenuate the degenerative phenotypes elicited by telomere dysfunction in the late-generation mTerc؊/؊ mice. Furthermore, in contrast to accelerated cancer onset and increased epithelial cancers of late-generation mTerc؊/؊ p53 mutant mice, late-generation mTerc؊/؊ Ink4a/Arf mutant mice experienced a delayed tumor onset and maintained the lymphoma and sarcoma spectrum. Consistent with the negligible role of Ink4a/Arf in the telomere checkpoint response in vivo, late-generation mTerc؊/؊ Ink4a/Arf؊/؊ tissues show activated p53, and derivative tumor cell lines sustain frequent loss of p53 function, whereas all early generation mTerc Ink4a/Arf؊/؊ tumor cell lines remain intact for p53. In addition, the late-generation mTerc؊/؊ Ink4a/Arf؊/؊ tumors showed activation of the alternative lengthening of telomere mechanism, underscoring the need for adaptation to the presence of telomere dysfunction in the absence of p16 Ink4a and p19 Arf . These observations highlight the importance of genetic context in dictating whether telomere dysfunction promotes or suppresses age-related degenerative conditions as well as the rate of initiation and type of spontaneous cancers.telomere ͉ cancer aging ͉ checkpoint ͉ p53

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…In line with this hypothesis, expression of Bmi-1 (a repressor of p16) promotes stem cell self-renewal in wildtype mice (Hosen et al, 2007). In contrast to aging of wild type mice, p16 and p19ARF deletion did not improve organ maintenance and lifespan of telomere dysfunctional mice indicating that this pathway is not a major component limiting stem cell function in response to telomere dysfunction (Khoo et al, 2007) .…”

“…(Molofsky et al, 2006;Krishnamurthy et al, 2006;Janzen et al, 2006;Stepanova and Sorrentino, 2005) No improvement in organ maintenance and lifespan in p16Ink4A, P19ARF compound mutant mice (Khoo et al, 2007) (Lynch and Lynch, 2005); Mismatch repair defect Colorectal cancer, extra-CRC cancers.…”

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…Indeed, lung emphysema and fibrosis are frequent in both G3 and later generations of TERC −/− independently by the p66SHC deletion, although we could not establish that lung dysfunction is the cause of death of these mice. Histiocytic sarcoma was reported to be the most frequent tumor lesion in C57Bl/6 mice, including p66SHC −/− (Ramsey et al ., 2014) and TERC −/− (Khoo et al ., 2007) models. In any case, the early mortality of TERC −/− mice is not determined by p66SHC suggesting that oxidative stress and telomere attrition do not cooperate to determine lifespan.…”

Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene

“…have elegantly shown that heterozygous loss of p53 in late generation mTerc À/À mice leads to the development of a 'humanized' spectrum of epithelial carcinomas, whereas homozygous loss of p53 in these animals leads to increased incidence of lymphomas. The tumor suppression effect of short telomeres is not affected by ATM and Ink4a/Arf deficiency, as delayed onset or decreased incidence of tumors or both were still observed in Atm Qi et al, 2003Qi et al, , 2005 and Ink4a/Arf (Greenberg et al, 1999;Khoo et al, 2007), respectively. The tumor suppressor activity of short telomeres is also abolished in mTerc À/À mice with deficiency of MSH2, a component in the mismatch repair (MMR) pathway (Martinez et al, 2009), WRN (Chang et al, 2004) or TRF2 overexpression .…”