Faculty Opinions recommendation of The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation.

ABSTRACT Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCP activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.

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Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins.

Molecular and Cellular Biology ◽

10.1128/mcb.16.6.2570 ◽

1996 ◽

Vol 16 (6) ◽

pp. 2570-2578 ◽

Cited By ~ 153

Author(s):

A Lasorella ◽

A Iavarone ◽

M A Israel

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cell Cycle Progression ◽

D1 Protein ◽

Protein Kinase Activity ◽

Cycle Progression ◽

Tumor Suppressor Proteins ◽

Cycle Arrest

Cells which are highly proliferative typically lack expression of differentiated, lineage-specific characteristics. Id2, a member of the helix-loop-helix (HLH) protein family known to inhibit cell differentiation, binds to the retinoblastoma protein (pRb) and abolishes its growth-suppressing activity. We found that Id2 but not Id1 or Id3 was able to bind in vitro not only pRb but also the related proteins p107 and p130. Also, an association between Id2 and p107 or p130 was observed in vivo in transiently transfected Saos-2 cells. In agreement with these results, expression of Id1 or Id3 did not affect the block of cell cycle progression mediated by pRb. Conversely, expression of Id2 specifically reversed the cell cycle arrest induced by each of the three members of the pRb family. Furthermore, the growth-suppressive activities of cyclin-dependent kinase inhibitors p16 and p21 were efficiently antagonized by high levels of Id2 but not by Id1 Id3. Consistent with the role of p16 as a selective inhibitor of pRb and pRb-related protein kinase activity, p16-imposed cell cycle arrest was completely abolished by Id2. Only a partial reversal of p21-induced growth suppression was observed, which correlated with the presence of a functional pRb. We also documented decreased levels of cyclin D1 protein and mRNA and the loss of cyclin D1-cdk4 complexes in cells constitutively expressing Id2. These data provide evidence for important Id2-mediated alterations in cell cycle components normally involved in the regulatory events of cell cycle progression, and they highlight a specific role for Id2 as an antagonist of multiple tumor suppressor proteins.

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The NF2 Tumor Suppressor Gene Product, Merlin, Inhibits Cell Proliferation and Cell Cycle Progression by Repressing Cyclin D1 Expression

Molecular and Cellular Biology ◽

10.1128/mcb.25.6.2384-2394.2005 ◽

2005 ◽

Vol 25 (6) ◽

pp. 2384-2394 ◽

Cited By ~ 119

Author(s):

Guang-Hui Xiao ◽

Ryan Gallagher ◽

Justin Shetler ◽

Kristine Skele ◽

Deborah A. Altomare ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Tumor Suppressor Gene ◽

Promoter Activity ◽

Cell Cycle Progression ◽

Malignant Tumors ◽

Suppressor Gene ◽

Cycle Progression

ABSTRACT Inactivation of the NF2 tumor suppressor gene has been observed in certain benign and malignant tumors. Recent studies have demonstrated that merlin, the product of the NF2 gene, is regulated by Rac/PAK signaling. However, the mechanism by which merlin acts as a tumor suppressor has remained obscure. In this report, we show that adenovirus-mediated expression of merlin in NF2-deficient tumor cells inhibits cell proliferation and arrests cells at G1 phase, concomitant with decreased expression of cyclin D1, inhibition of CDK4 activity, and dephosphorylation of pRB. The effect of merlin on cell cycle progression was partially overridden by ectopic expression of cyclin D1. RNA interference experiments showed that silencing of the endogenous NF2 gene results in upregulation of cyclin D1 and S-phase entry. Furthermore, PAK1-stimulated cyclin D1 promoter activity was repressed by cotransfection of NF2, and PAK activity was inhibited by expression of merlin. Interestingly, the S518A mutant form of merlin, which is refractory to phosphorylation by PAK, was more efficient than the wild-type protein in inhibiting cell cycle progression and in repressing cyclin D1 promoter activity. Collectively, our data indicate that merlin exerts its antiproliferative effect, at least in part, via repression of PAK-induced cyclin D1 expression, suggesting a unifying mechanism by which merlin inactivation might contribute to the overgrowth seen in both noninvasive and malignant tumors.

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The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation

Molecular and Cellular Biology ◽

10.1128/mcb.22.12.4309-4318.2002 ◽

2002 ◽

Vol 22 (12) ◽

pp. 4309-4318 ◽

Cited By ~ 235

Author(s):

Latha Shivakumar ◽

John Minna ◽

Toshiyuki Sakamaki ◽

Richard Pestell ◽

Michael A. White

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Cell Cycle Progression ◽

S Phase ◽

Phase Cell ◽

Cycle Progression ◽

Cycle Arrest

ABSTRACT The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G1/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G1/S-phase cell cycle progression.

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PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Oncogene ◽

10.1038/s41388-021-01881-8 ◽

2021 ◽

Author(s):

Michael J. O’Connor ◽

Tanay Thakar ◽

Claudia M. Nicolae ◽

George-Lucian Moldovan

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Promote Cell Cycle Progression

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The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death

Oncogene ◽

10.1038/sj.onc.1202910 ◽

1999 ◽

Vol 18 (37) ◽

pp. 5239-5245 ◽

Cited By ~ 30

Author(s):

Karen E Knudsen ◽

Erich Weber ◽

Karen C Arden ◽

Webster K Cavenee ◽

James R Feramisco ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Tumor Suppressor ◽

Cell Cycle Progression ◽

Cellular Proliferation ◽

Cycle Progression ◽

Retinoblastoma Tumor Suppressor ◽

Retinoblastoma Tumor

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

Molecular and Cellular Biology ◽

10.1128/mcb.00046-18 ◽

2018 ◽

Vol 38 (17) ◽

Cited By ~ 2

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.

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