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Induction of p202, a modulator of apoptosis, during oncogenic transformation of NIH 3T3 cells by activated H‐Ras (Q61L) contributes to cell survival
Author(s) -
Xin Hong,
Geng Yanbiao,
Pramanik Rocky,
Choubey Divaker
Publication year - 2002
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10372
Subject(s) - 3t3 cells , microbiology and biotechnology , apoptosis , reporter gene , transcription factor , cell culture , biology , cell , cell growth , chemistry , gene expression , gene , transfection , biochemistry , genetics
Previous studies have revealed that p202 (52 kDa), an interferon (IFN) and differentiation‐inducible protein, negatively regulates cell proliferation and modulates cell survival. However, the role of p202 in transformed cells remains to be investigated. Here we report that constitutive expression of oncogenic H‐Ras (Q61L) in NIH 3T3 cells, which resulted in cell transformation, was associated with increases in the steady‐state levels of 202 RNA and protein. Interestingly, the increase in p202 levels in transformed cells correlated with increases in the activity of the transcription factor c‐Jun/AP‐1, which bound to the two potential AP‐1 DNA binding sites (the AP‐1CS1 and AP‐1CS2) in the 5′‐regulatory region of the 202 gene in gel mobility shift assays. Furthermore, the site‐directed mutagenesis, coupled with promoter‐reporter analyses, revealed that these two AP‐1 DNA binding sites contribute to the regulation of the 202 gene in Ras transformed cells. Because treatment of transformed cells with a specific inhibitor of MEK (PD 98059) resulted in significant decreases in the levels of p202, these observations raise the possibility that in transformed cells Ras/Raf/MEK pathway regulates the transcriptional activation of the 202 gene. Significantly, decreases in the levels of p202 in Ras transformed NIH 3T3 cells under reduced serum conditions increased the susceptibility to apoptosis. Collectively, our observations support the idea that the transcriptional increases in the levels of p202 by oncogenic H‐Ras in NIH 3T3 cells are needed for cell survival. © 2002 Wiley‐Liss, Inc.