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Inorganic arsenic exposure induces E 2 F ‐dependent G 0/ G 1 arrest via an increase in retinoblastoma family protein p130 in B ‐cell lymphoma A 20 cells
Author(s) -
Okamura Kazuyuki,
Miki Daisuke,
Nohara Keiko
Publication year - 2013
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12079
Subject(s) - arsenite , e2f , retinoblastoma protein , biology , cell cycle , proteasome , microbiology and biotechnology , cell cycle checkpoint , cancer research , cell , chemistry , biochemistry , arsenic , organic chemistry
Inorganic arsenic exerts toxic effect on multiple systems including the immune system. We previously showed in a study on mouse thymocytes and B ‐cell lymphoma A 20 cells that arsenite induces cell cycle arrest at G 0/ G 1 by suppressing expression of E 2 F ‐target genes. In this study, we furthermore investigated the involvement of retinoblastoma ( RB ) family proteins in E 2 F ‐dependent cell cycle arrest by arsenite. Arsenite exposure of A 20 cells was showed to increase the protein level of p130, a RB family member, without changing the m RNA level. Suppression of arsenite‐induced p130 by si RNA reduced the G 0/ G 1 phase, indicating that p130 accumulation is responsible for arsenite‐induced G 0/ G 1 arrest. The accumulated p130 was shown to increase the p130 complex with E 2 F 4, a transcription‐suppressing E 2 F . Comparison by W estern blotting of arsenite‐induced p130 and p130 accumulated by a proteasome inhibitor suggested that arsenite‐induced p130 is hypophosphorylated and hypoubiquitinated and refractory to proteasome‐dependent degradation. We also showed that arsenite increases m RNA and protein of p16 INK4a , an inhibitor of CDK 4/6 that phosphorylates p130. Down‐regulation of arsenite‐induced p16 INK4a by si RNA suppressed the p130 accumulation. We propose a novel mechanism in which arsenite inhibits phosphorylation/ubiquitin‐dependent proteasome degradation of p130 by inducing p16 INK4a and the accumulated p130 causes cell cycle arrest with E 2 F 4.