OVERCOMING SENESCENCE REQUIRES ALTERATIONS IN THE p16/pRb PATHWAY IN PROSTATE EPITHELIAL CELLS

Jarrard, David; Yeager, Thomas R.; Shi, Yan; Kinoshita, Hidefumi; Sarkar, Somdatta; Meisner, Lorraine F.; Resnikoff, Catherine; Magrane, Gregg

doi:10.1097/00005392-199904010-00498

Cited by 10 publications

(17 citation statements)

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“…How aging contributes to PCa development remains an enigma. Cultured NHP cells undergo replicative senescence after a period of proliferation and the process seems to involve the activation of both p16/pRb and p53/p21 pathways (Jarrard et al, 1999;Sandhu et al, 2000;Schwarze et al, 2001;Untergasser et al, 2002). Since replicative senescence is considered a barrier to immortalization and transformation (Hanahan and Weinberg, 2000;Wright and Shay, 2001;Schmitt et al, 2002), it is not surprising that multiple molecules (e.g., Rb, p53, and p16) involved in regulating cell senescence have been implicated in PCa development.…”

Section: Introductionmentioning

confidence: 99%

Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

et al. 2005

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Normal human prostatic (NHP) epithelial cells undergo senescence in vitro and in vivo, but little is known about the tissue-specific molecular mechanisms. Here we first characterize young primary NHP cells as CK5 þ /CK18 þ intermediate basal cells that also express several other putative stem/progenitor cell markers including p63, CD44, a2b1, and hTERT. When cultured in serum-and androgen-free medium, NHP cells gradually lose the expression of these markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-lipoxygenase 2 (15-LOX2), a molecule with a restricted tissue expression and most abundantly expressed in adult human prostate, in the replicative senescence of NHP cells. First, the 15-LOX2 promoter activity and the mRNA and protein levels of 15-LOX2 and its multiple splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner. Second, all immortalized prostate epithelial cells and prostate cancer cells do not express 15-LOX2. Third, PCa cells stably transfected with 15-LOX2 or 15-LOX2sv-b, a splice variant that does not possess arachidonate-metabolizing activity, show a passage-related senescence-like phenotype. Fourth, infection of early-passage NHP cells with retroviral vectors encoding 15-LOX2 or 15-LOX2sv-b induces partial cellcycle arrest and big and flat senescence-like phenotype. Finally, 15-LOX2 protein expression in human prostate correlates with age. Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence.

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Section: Introductionmentioning

confidence: 99%

Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

et al. 2005

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“…Most epithelial cells, propagated in standard cultured conditions, undergo a growth arrest early in their lifespan, well before telomeres become short enough to elicit a telomere-dependent response. Since this premature growth arrest cannot be explained in terms of telomere shortening, several groups have proposed that a telomere-independent process involving the p16/RB pathway prevents cells from proliferating beyond 10-20 doublings, and that immortalization requires the inactivation of two different mechanisms: a p16/RB pathway and telomere shortening (Kiyono et al, 1998;Jarrard et al, 1999;Dickson et al, 2000;Farwell et al, 2000;Jones et al, 2000). The premature growth arrest in human mammary epithelial cells (HMECs) has been called self-selection or mortality stage 0 (M0).…”

Section: Introductionmentioning

confidence: 99%

Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells

et al. 2003

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Many stimuli causing 'stress' or DNA damage in cells can produce phenotypes that overlap with telomere-based replicative senescence. In epithelial systems, the p16/RB pathway may function as a stress senescence-signaling pathway independent of telomere shortening. Overexpressing cyclin-dependent kinase 4 (Cdk4) in human epidermal keratinocytes and human mammary epithelial cells not only prevents the p16 INK4a -associated premature growth arrest due to telomere-independent stress (e.g., inadequate culture conditions), but also bypasses the ensuing telomere-dependent senescence (M1). Overexpressed Cdk4 in epithelial cells induces a dramatic upregulation of p16 INK4a and milder upregulation of p53 and p21 WAF1 , which become unresponsive to UV irradiation. Despite the high levels of these checkpoint factors, Cdk4-overexpressing cells divide in an apparently normal regulated fashion, are able to respond to changes in calcium levels, retain the stem cell phenotype, and fully differentiate and stratify. These results suggest that the differentiation pathways in Cdk4-overexpressing cells remain intact.

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“…Several studies have demonstrated that inactivation of the Rb/ p16 tumor suppressor pathway is required for immortalization of non-cancer cells (Jarrard et al, 1999). Promoter methylation and transcriptional repression of p16 has been reported after several passages of human mammary epithelial cells (Foster et al, 1998).…”

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confidence: 99%

Aberrant CpG island methylation in cancer cell lines arises in the primary cancers from which they were derived

et al. 2002

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A higher prevalence of epigenetic inactivation of tumor suppressor genes has been reported in cancer cell line populations compared to primary cancer populations. Cancer-related genes are commonly methylated in cancer cell lines but it is not known the extent to which tumor suppressor genes may be arti®cially methylated in vitro. We therefore examined 10 pancreatic cancer cell lines and corresponding primary tumors for aberrant DNA methylation of promoter CpG islands of eight genes and seven CpG islands. Using methylation-speci®c PCR (MSP), methylation was not detected at any of the 15 CpG islands in 15 normal pancreata or in an immortalized normal pancreatic duct epithelial (HPDE) cell line. Of 150 loci examined, 49 loci were methylated in both primary carcinomas and their corresponding cell lines, 95 loci were not methylated in either cell lines or their corresponding primary carcinomas. There were four loci methylated only in cell lines while another two loci were methylated only in primary carcinomas. Overall, the methylation status of primary carcinomas and their cell lines were concordant in 96% of cases (144 of 150) (J statistic; J=0.92, P50.0001). We conclude that most of the DNA methylation of tumor suppressor genes observed in cancer cell lines is present in the primary carcinomas from which they were derived.

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OVERCOMING SENESCENCE REQUIRES ALTERATIONS IN THE p16/pRb PATHWAY IN PROSTATE EPITHELIAL CELLS

Cited by 10 publications

References 0 publications

Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells

Aberrant CpG island methylation in cancer cell lines arises in the primary cancers from which they were derived

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