The p16<SUP>INK4a</SUP>-RB pathway : molecular link between cellular senescence and tumor suppression

ABSTRACT Inactivation of the Rb-mediated G1 control pathway is a common event found in many types of human tumors. To test how the Rb pathway interacts with other pathways in tumor suppression, we characterized mice with mutations in both the cyclin-dependent kinase (CDK) inhibitor p18 Ink4c and the lipid phosphatase Pten, which regulates cell growth. The double mutant mice develop a wider spectrum of tumors, including prostate cancer in the anterior and dorsolateral lobes, with nearly complete penetrance and at an accelerated rate. The remaining wild-type allele of Pten was lost at a high frequency in Pten +/− cells but not in p18 +/− Pten +/− or p18 −/− Pten +/− prostate tumor cells, nor in other Pten +/− tumor cells, suggesting a tissue- and genetic background-dependent haploinsufficiency of Pten in tumor suppression. p18 deletion, CDK4 overexpression, or oncoviral inactivation of Rb family proteins caused activation of Akt/PKB that was recessive to the reduction of PTEN activity. We suggest that p18 and Pten cooperate in tumor suppression by constraining a positive regulatory loop between cell growth and cell cycle control pathways.

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Abstract 1264: Conditional mouse and zebrafish models of INK4-mediated tumor suppression reveal ARF-independent regulation of cellular senescence

10.1158/1538-7445.am2015-1264 ◽

2015 ◽

Cited By ~ 1

Author(s):

Kathleen Flaherty ◽

Daniel Jones ◽

Shamila Yussuf ◽

Stephani Davis ◽

Eric Huselid ◽

...

Keyword(s):

Cellular Senescence ◽

Tumor Suppression

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Abstract 5483: Investigating the role of the retinoblastoma protein in induction and maintenance of oncogene-induced cellular senescence in tumor suppression

10.1158/1538-7445.am2017-5483 ◽

2017 ◽

Cited By ~ 1

Author(s):

Mohamad Harajly ◽

Hasan Zalzali ◽

Farah Ghamloush ◽

Raya H. Saab

Keyword(s):

Cellular Senescence ◽

Tumor Suppression ◽

Retinoblastoma Protein

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BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

Molecular and Cellular Biology ◽

10.1128/mcb.01744-12 ◽

2013 ◽

Vol 33 (9) ◽

pp. 1819-1829 ◽

Cited By ~ 28

Author(s):

Zhigang Tu ◽

Xinying Zhuang ◽

Yong-Gang Yao ◽

Rugang Zhang

Keyword(s):

Dna Damage ◽

Molecular Mechanism ◽

Chromatin Remodeling ◽

Cellular Senescence ◽

Chromatin Immunoprecipitation ◽

Tumor Suppression ◽

Gene Promoters ◽

Independent Manner ◽

Oncogenic Ras ◽

Suppression Mechanism

Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of s enescence- a ssociated h eterochromatin f oci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21 CIP1 , and p16 INK4a , but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.

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Lysyl Oxidase, Cellular Senescence and Tumor Suppression

Bioscience Reports ◽

10.1023/a:1027361418200 ◽

1997 ◽

Vol 17 (4) ◽

pp. 409-414 ◽

Cited By ~ 12

Author(s):

Rashmi Sharma ◽

Jeffrey A. Kramer ◽

Stephen A. Krawetz

Keyword(s):

Extracellular Matrix ◽

Cell Lines ◽

Cellular Senescence ◽

Tumor Suppression ◽

Replicative Senescence ◽

Lysyl Oxidase ◽

Normal Fibroblast ◽

Northern Hybridization ◽

Type Iii Collagen

Replicative senescence may provide a mechanism of tumor suppression and tumor suppressor genes of the extracellular matrix, like lysyl oxidase, may play a role in cellular senescence. To test this hypothesis and determine whether the extracellular matrix may serve as a marker, the steady-state levels of human lysyl oxidase, α-I type III collagen and β-actin transcripts were assessed in various cell lines during in vitro passge. Northern hybridization analysis showed a significant increase in the levels of progeria fibroblast extracellular matrix mRNAs immediately preceding senescence. The levels of these mRNAs were unaffected in age-matched normal fibroblast and fetal fibroblast cell lines.

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