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

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.

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Inactivation of CtIP Leads to Early Embryonic Lethality Mediated by G1 Restraint and to Tumorigenesis by Haploid Insufficiency

Molecular and Cellular Biology ◽

10.1128/mcb.25.9.3535-3542.2005 ◽

2005 ◽

Vol 25 (9) ◽

pp. 3535-3542 ◽

Cited By ~ 94

Author(s):

Phang-Lang Chen ◽

Feng Liu ◽

Suna Cai ◽

Xiaoqin Lin ◽

Aihua Li ◽

...

Keyword(s):

Cell Cycle ◽

Transcriptional Repression ◽

Cell Cycle Progression ◽

Tumor Formation ◽

3T3 Cells ◽

Embryonic Fibroblasts ◽

Cycle Progression ◽

Early Embryonic Lethality ◽

Nih 3T3 ◽

Regulate Cell Cycle Progression

ABSTRACT CtIP interacts with a group of tumor suppressor proteins including RB (retinoblastoma protein), BRCA1, Ikaros, and CtBP, which regulate cell cycle progression through transcriptional repression as well as chromatin remodeling. However, how CtIP exerts its biological function in cell cycle progression remains elusive. To address this issue, we generated an inactivated Ctip allele in mice by inserting a neo gene into exon 5. The corresponding Ctip − / − embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G1, leading to a slightly elevated cell death. Mouse NIH 3T3 cells depleted of Ctip were arrested at G1 with the concomitant increase in hypophosphorylated Rb and Cdk inhibitors, p21. However, depletion of Ctip failed to arrest Rb − / − mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G1, suggesting that this arrest is RB dependent. Importantly, the life span of Ctip +/ − heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas. The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Taken together, this finding uncovers a novel G1/S regulation in that CtIP counteracts Rb-mediated G1 restraint. Deregulation of this function leads to a defect in early embryogenesis and contributes, in part, to tumor formation.

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Platelet-derived extracellular vesicles regulate cell cycle progression and cell migration in breast cancer cells

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/j.bbamcr.2020.118886 ◽

2021 ◽

Vol 1868 (1) ◽

pp. 118886

Author(s):

Mauro Vismara ◽

Marta Zarà ◽

Sharon Negri ◽

Jessica Canino ◽

Ilaria Canobbio ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Migration ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Breast Cancer Cells ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Regulate Cell Cycle Progression

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B Lymphocytes Differentially Use the Rel and Nuclear Factor κB1 (NF-κB1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.5.663 ◽

1998 ◽

Vol 187 (5) ◽

pp. 663-674 ◽

Cited By ~ 169

Author(s):

Raelene J. Grumont ◽

Ian J. Rourke ◽

Lorraine A. O'Reilly ◽

Andreas Strasser ◽

Kensuke Miyake ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Transcription Factors ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Cell Cycle Progression ◽

Nuclear Factor ◽

Cycle Progression ◽

Regulate Cell Cycle Progression

Rel and nuclear factor (NF)-κB1, two members of the Rel/NF-κB transcription factor family, are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-κB1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1−/− mice, the level of apoptosis in cultures of quiescent nfkb1−/−, but not c-rel−/−, B cells is higher. The failure of c-rel−/− or nfkb1−/− B cells to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel−/− and nfkb1−/− B cells, but does not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not simply a consequence of apoptosis and that Rel/NF-κB proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-κB–dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel−/− B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells, NF-κB1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli requires different Rel/NF-κB factors to control cell cycle progression and prevent apoptosis.

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Regulation of CDK7–Carboxyl-Terminal Domain Kinase Activity by the Tumor Suppressor p16INK4A Contributes to Cell Cycle Regulation

Molecular and Cellular Biology ◽

10.1128/mcb.20.20.7726-7734.2000 ◽

2000 ◽

Vol 20 (20) ◽

pp. 7726-7734 ◽

Cited By ~ 13

Author(s):

Eiji Nishiwaki ◽

Saralinda L. Turner ◽

Susanna Harju ◽

Shiro Miyazaki ◽

Masahide Kashiwagi ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Rna Polymerase Ii ◽

Cell Cycle Progression ◽

Kinase Activity ◽

Alternative Pathway ◽

Cycle Progression ◽

Terminal Domain ◽

Carboxyl Terminal Domain ◽

Carboxyl Terminal

ABSTRACT The eukaryotic cell cycle is regulated by cyclin-dependent kinases (CDKs). CDK4 and CDK6, which are activated by D-type cyclins during the G1 phase of the cell cycle, are thought to be responsible for phosphorylation of the retinoblastoma gene product (pRb). The tumor suppressor p16INK4A inhibits phosphorylation of pRb by CDK4 and CDK6 and can thereby block cell cycle progression at the G1/S boundary. Phosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II by general transcription factor TFIIH is believed to be an important regulatory event in transcription. TFIIH contains a CDK7 kinase subunit and phosphorylates the CTD. We have previously shown that p16INK4A inhibits phosphorylation of the CTD by TFIIH. Here we report that the ability of p16INK4A to inhibit CDK7-CTD kinase contributes to the capacity to induce cell cycle arrest. These results suggest that p16INK4A may regulate cell cycle progression by inhibiting not only CDK4-pRb kinase activity but also by modulating CDK7-CTD kinase activity. Regulation of CDK7-CTD kinase activity by p16INK4A thus may represent an alternative pathway for controlling cell cycle progression.

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