Irreversibility of cellular senescence: dual roles of p16INK4a/Rb-pathway in cell cycle control

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.

Download Full-text

First-in-human phase I study of SY-5609, an oral, potent, and selective noncovalent CDK7 inhibitor, in adult patients with select advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps3662 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS3662-TPS3662 ◽

Cited By ~ 1

Author(s):

Kyriakos P. Papadopoulos ◽

Manish Sharma ◽

Erika Paige Hamilton ◽

Debra L. Richardson ◽

Graeme Hodgson ◽

...

Keyword(s):

Cell Cycle ◽

Antitumor Activity ◽

Solid Tumors ◽

Cell Cycle Control ◽

Single Agent ◽

Genetic Alterations ◽

Adult Patients ◽

Molecular Evidence ◽

Advanced Solid Tumors ◽

Rb Pathway

TPS3662 Background: SY-5609 is an oral, noncovalent, highly selective and potent inhibitor of cyclin-dependent kinase 7 (CDK7), a key regulator of 2 biological processes that play critical roles in driving tumor development: transcription and cell cycle control. Evaluation of SY-5609 as a single agent in PDX models from a range of solid tumors, including breast, ovarian, lung and colorectal tumors, revealed robust antitumor activity including complete regressions, and activity in models known to be resistant to standard of care therapy. Models with genetic alterations in RB pathway genes demonstrated deep ( > 90% TGI) and sustained SY-5609-induced tumor regressions following treatment discontinuation, in contrast to models without genetic alteration in RB pathway genes, suggesting that tumor cells with aberrant cell-cycle control may be particularly sensitive to SY-5609 treatment. The study is designed to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of SY-5609, to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and preliminary antitumor activity of SY-5609, and to explore candidate biomarkers predictive of response to SY-5609. Methods: This is a multi-center, open-label Phase 1 trial expected to enroll approximately 60 adult patients with select advanced solid tumors for which standard treatment is no longer effective. The dose escalation phase of the trial is open to adult patients with ovarian, breast, colorectal, or lung cancer, and patients with any solid tumor histology with molecular evidence of deregulated RB cell cycle control. SY-5609 is being administered orally once daily, for each 4-week cycle. Initially, patients will be enrolled into single-patient accelerated titration cohorts; subsequent cohorts will transition to a 3 + 3 design. Following completion of DLT evaluation at a given dose level, additional patients may be enrolled at that dose to further characterize safety, PK, PD, and early clinical activity. Data from this trial will support dose selection for planned evaluations of antitumor activity of SY-5609 as a single agent and in combination. Clinical trial information: NCT04247126 .

Download Full-text

14-3-3σ gene silencing during melanoma progression and its role in cell cycle control and cellular senescence

Molecular Cancer ◽

10.1186/1476-4598-8-53 ◽

2009 ◽

Vol 8 (1) ◽

pp. 53 ◽

Cited By ~ 28

Author(s):

Julia Schultz ◽

Saleh M Ibrahim ◽

Julio Vera ◽

Manfred Kunz

Keyword(s):

Cell Cycle ◽

Gene Silencing ◽

Cellular Senescence ◽

Cell Cycle Control ◽

Melanoma Progression

Download Full-text

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

Frontiers in Genetics ◽

10.3389/fgene.2021.597566 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yongjin Zhang ◽

Chihao Shao ◽

Haili Li ◽

Kun Wu ◽

Lixin Gong ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Stem Cell ◽

Cellular Senescence ◽

Cellular Proliferation ◽

Werner Syndrome ◽

Survival Curve ◽

Cell Cycle Control ◽

Tissue Homeostasis ◽

Premature Aging

Human Werner syndrome (WS) is an autosomal recessive progeria disease. A mouse model of WS manifests the disease through telomere dysfunction-induced aging phenotypes, which might result from cell cycle control and cellular senescence. Both p21Waf1/Cip1 (p21, encoded by the Cdkn1a gene) and p16Ink4a (p16, encoded by the Ink4a gene) are cell cycle inhibitors and are involved in regulating two key pathways of cellular senescence. To test the effect of p21 and p16 deficiencies in WS, we crossed WS mice (DKO) with p21–/– or p16–/– mice to construct triple knockout (p21-TKO or p16-TKO) mice. By studying the survival curve, bone density, regenerative tissue (testis), and stem cell capacity (intestine), we surprisingly found that p21-TKO mice displayed accelerated premature aging compared with DKO mice, while p16-TKO mice showed attenuation of the aging phenotypes. The incidence of apoptosis and cellular senescence were upregulated in p21-TKO mice tissue and downregulated in p16-TKO mice. Surprisingly, cellular proliferation in p21-TKO mice tissue was also upregulated, and the p21-TKO mice did not show telomere shortening compared with age-matched DKO mice, although p16-TKO mice displayed obvious enhancement of telomere lengthening. Consistent with these phenotypes, the SIRT1-PGC1 pathway was upregulated in p16-TKO but downregulated in p21-TKO compared with DKO mouse embryo fibroblasts (MEFs). However, the DNA damage response pathway was highly activated in p21-TKO, but rescued in p16-TKO, compared with DKO MEFs. These data suggest that p21 protected the stem cell reservoir by regulating cellular proliferation and turnover at a proper rate and that p21 loss in WS activated fairly severe DNA damage responses (DDR), which might cause an abnormal increase in tissue homeostasis. On the other hand, p16 promoted cellular senescence by inhibiting cellular proliferation, and p16 deficiency released this barrier signal without causing severe DDR.

Download Full-text