Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits

Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I.

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ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.20.1.233-241.2000 ◽

2000 ◽

Vol 20 (1) ◽

pp. 233-241 ◽

Cited By ~ 72

Author(s):

Zhengming Gu ◽

Cathy Flemington ◽

Thomas Chittenden ◽

Gerard P. Zambetti

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Tumor Suppressor ◽

Cell Cycle Arrest ◽

Apoptotic Cell ◽

Functional Characterization ◽

Growth Control ◽

P53 Tumor Suppressor ◽

Cycle Arrest ◽

P53 Response

ABSTRACT DNA damage and/or hyperproliferative signals activate the wild-type p53 tumor suppressor protein, which induces a G1 cell cycle arrest or apoptosis. Although the mechanism of p53-mediated cell cycle arrest is fairly well defined, the p53-dependent pathway regulating apoptosis is poorly understood. Here we report the functional characterization of murine ei24 (also known asPIG8), a gene directly regulated by p53, whose overexpression negatively controls cell growth and induces apoptotic cell death. Ectopic ei24 expression markedly inhibits cell colony formation, induces the morphological features of apoptosis, and reduces the number of β-galactosidase-marked cells, which is efficiently blocked by coexpression of Bcl-XL. Theei24/PIG8 gene is localized on human chromosome 11q23, a region frequently altered in human cancers. These results suggest that ei24 may play an important role in negative cell growth control by functioning as an apoptotic effector of p53 tumor suppressor activities.

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Artemisinin triggers a G1 cell cycle arrest of human Ishikawa endometrial cancer cells and inhibits cyclin-dependent kinase-4 promoter activity and expression by disrupting nuclear factor-κB transcriptional signaling

Anti-Cancer Drugs ◽

10.1097/cad.0000000000000054 ◽

2014 ◽

Vol 25 (3) ◽

pp. 270-281 ◽

Cited By ~ 25

Author(s):

Kalvin Q. Tran ◽

Antony S. Tin ◽

Gary L. Firestone

Keyword(s):

Cell Cycle ◽

Endometrial Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Promoter Activity ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Cyclin Dependent Kinase ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest

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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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