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Gene 33 mediates Cr(VI)‐induced DNA damage response
Author(s) -
Park Soyoung,
Li Cen,
Zhao Hong,
Darzynkiewicz Zbigniew,
Xu Dazhong
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.54.3
Subject(s) - dna damage , gene knockdown , a549 cell , cell cycle , microbiology and biotechnology , cell cycle checkpoint , apoptosis , biology , carcinogenesis , chemistry , cancer research , signal transduction , cell growth , gene , dna , genetics
Hexavalent chromium [Cr(VI)] is a known human lung carcinogen. But, the molecular players that mediate its carcinogenesis are poorly defined. Gene 33 (Mig‐6, ERRFI1) is an adaptor protein implicated in lung cancer. It regulates multiple signaling pathways mediating cell proliferation, migration, apoptosis, and senescence. In this study, we found that Cr(VI) triggers a typical DNA damage response in BEAS‐2B lung epithelial cells, manifested as elevation of γH2AX and P‐p53(S15) levels, in a dose‐dependent fashion. The Cr(VI)‐induced DNA damage response appeared mainly in the S and G2/M phases of the cell cycle. However, the dose‐dependent increase in the γH2AX level was more pronounced in G1 and S phases than in the G2/M phase. In contrast, P‐p53(S15) signals changed more uniformly in all phases of the cell cycle. Cr(VI) also induced the DNA damage response in A549 lung carcinoma cells. Gene 33 knockdown with siRNA significantly inhibited Cr(VI)‐induced γH2AX signals in A549. More interestingly, inhibition of the γH2AX signal by Gene 33 knockdown mainly occurred in G1 and G2/M phases of the cell cycle. In contrast, P‐p53(S15) signals were dramatically elevated by Gene 33 knockdown. In addition, the level of Gene 33 protein was suppressed by Cr(VI) treatments. Moreover, ectopic overexpression of Gene 33 elevates the basal γH2AX level while having limited effect on the P‐p53(S15) signal in A549 cells. Surprisingly, Gene 33 containing a point mutation disrupting its interaction with EGFR elicited much stronger increases in basal γH2AX and P‐p53(S15) levels. Our results revealed a novel and apparently complex function of Gene 33 in mediating the DNA damage response and a potential involvement of this protein in Cr(VI)‐mediated carcinogenesis.