scholarly journals Cyclin D activates the Rb tumor suppressor by mono-phosphorylation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Anil M Narasimha ◽  
Manuel Kaulich ◽  
Gary S Shapiro ◽  
Yoon J Choi ◽  
Piotr Sicinski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Active Form ◽  
Biologically Active ◽  
G1 Phase ◽  
Cycle Progression ◽  
Restriction Point ◽  
Damage Response ◽  
E2f Transcription Factors

The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, to release E2F transcription factors. However, this model remains unproven biochemically and the biologically active form(s) of Rb remains unknown. In this study, we find that Rb is exclusively mono-phosphorylated in early G1 phase by cyclin D:Cdk4/6. Mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but show preferential E2F binding patterns. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by quantum hyper-phosphorylation. Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription, whereas cells undergoing differentiation utilize un-phosphorylated Rb. These observations fundamentally change our understanding of G1 cell cycle progression and show that mono-phosphorylated Rb, generated by cyclin D:Cdk4/6, is the only Rb isoform in early G1 phase.

scholarly journals The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and Cell Cycle Progression via Retinoblastoma Protein

2018 ◽  
Vol 38 (17) ◽  
Author(s):  
Shakhawoat Hossain ◽  
Hiroaki Iwasa ◽  
Aradhan Sarkar ◽  
Junichi Maruyama ◽  
Kyoko Arimoto-Matsuzaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Loss Of Function ◽  
Cycle Progression ◽  
P53 Expression ◽  
Cycle Arrest ◽  
Hct116 Cells

ABSTRACT RASSF6 is a member of the tumor suppressor Ras association domain family (RASSF) proteins. RASSF6 is frequently suppressed in human cancers, and its low expression level is associated with poor prognosis. RASSF6 regulates cell cycle arrest and apoptosis and plays a tumor suppressor role. Mechanistically, RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. However, RASSF6 also induces cell cycle arrest and apoptosis in a p53-negative background, which implies that the tumor suppressor function of RASSF6 does not depend solely on p53. In this study, we revealed that RASSF6 mediates cell cycle arrest and apoptosis via pRb. RASSF6 enhances the interaction between pRb and protein phosphatase. RASSF6 also enhances P16INK4A and P14ARF expression by suppressing BMI1. In this way, RASSF6 increases unphosphorylated pRb and augments the interaction between pRb and E2F1. Moreover, RASSF6 induces TP73 target genes via pRb and E2F1 in a p53-negative background. Finally, we confirmed that RASSF6 depletion induces polyploid cells in p53-negative HCT116 cells. In conclusion, RASSF6 behaves as a tumor suppressor in cancers with loss of function of p53, and pRb is implicated in this function of RASSF6.

scholarly journals The Licensing Factor Cdt1 Links Cell Cycle Progression to the DNA Damage Response

2020 ◽  
Vol 40 (5) ◽  
pp. 2449-2456
Author(s):  
ALEXANDRA KANELLOU ◽  
NICKOLAOS NIKIFOROS GIAKOUMAKIS ◽  
ANDREAS PANAGOPOULOS ◽  
SPYRIDON CHAMPERIS TSANIRAS ◽  
ZOI LYGEROU
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Damage Response ◽  
Licensing Factor

scholarly journals Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 140156 ◽  
Author(s):  
Didier J. Colin ◽  
Karolina O. Hain ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinases ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anti Cancer ◽  
Damage Response ◽  
Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

scholarly journals Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.

1993 ◽  
Vol 13 (6) ◽  
pp. 3577-3587 ◽  
Author(s):  
E A Musgrove ◽  
J A Hamilton ◽  
C S Lee ◽  
K J Sweeney ◽  
C K Watts ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cell Cycle Progression ◽  
S Phase ◽  
G1 Phase ◽  
Cycle Progression

Cyclins and proto-oncogenes including c-myc have been implicated in eukaryotic cell cycle control. The role of cyclins in steroidal regulation of cell proliferation is unknown, but a role for c-myc has been suggested. This study investigated the relationship between regulation of T-47D breast cancer cell cycle progression, particularly by steroids and their antagonists, and changes in the levels of expression of these genes. Sequential induction of cyclins D1 (early G1 phase), D3, E, A (late G1-early S phase), and B1 (G2 phase) was observed following insulin stimulation of cell cycle progression in serum-free medium. Transient acceleration of G1-phase cells by progestin was also accompanied by rapid induction of cyclin D1, apparent within 2 h. This early induction of cyclin D1 and the ability of delayed administration of antiprogestin to antagonize progestin-induced increases in both cyclin D1 mRNA and the proportion of cells in S phase support a central role for cyclin D1 in mediating the mitogenic response in T-47D cells. Compatible with this hypothesis, antiestrogen treatment reduced the expression of cyclin D1 approximately 8 h before changes in cell cycle phase distribution accompanying growth inhibition. In the absence of progestin, antiprogestin treatment inhibited T-47D cell cycle progression but in contrast did not decrease cyclin D1 expression. Thus, changes in cyclin D1 gene expression are often, but not invariably, associated with changes in the rate of T-47D breast cancer cell cycle progression. However, both antiestrogen and antiprogestin depleted c-myc mRNA by > 80% within 2 h. These data suggest the involvement of both cyclin D1 and c-myc in the steroidal control of breast cancer cell cycle progression.

scholarly journals The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth

Oncogene ◽  
2015 ◽  
Vol 35 (24) ◽  
pp. 3114-3124 ◽  
Author(s):  
E Palazzo ◽  
M Kellett ◽  
C Cataisson ◽  
A Gormley ◽  
P W Bible ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Tumor Suppressor P53 ◽  
Cycle Progression ◽  
Regulate Cell Cycle Progression
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