The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins.
Mutant p53 proteins (mutp53) often acquire oncogenic activities, conferring drug resistance and/or promoting cancer cell migration and invasion. Although it has been well established that such a gain of function is mainly achieved through interaction with transcriptional regulators, thereby modulating cancer-associated gene expression, how the mutp53 function is regulated remains ... elusive. Here we report that activating transcription factor 3 (ATF3) bound common mutp53 (e.g. R175H and R273H) and, subsequently, suppressed their oncogenic activities. ATF3 repressed mutp53-induced NFKB2 expression and sensitized R175H-expressing cancer cells to cisplatin and etoposide treatments. Moreover, ATF3 appeared to suppress R175H- and R273H-mediated cancer cell migration and invasion as a consequence of preventing the transcription factor p63 from inactivation by mutp53. Accordingly, ATF3 promoted the expression of the metastasis suppressor SHARP1 in mutp53-expressing cells. An ATF3 mutant devoid of the mutp53-binding domain failed to disrupt the mutp53-p63 binding and, thus, lost the activity to suppress mutp53-mediated migration, suggesting that ATF3 binds to mutp53 to suppress its oncogenic function. In line with these results, we found that down-regulation of ATF3 expression correlated with lymph node metastasis in TP53-mutated human lung cancer. We conclude that ATF3 can suppress mutp53 oncogenic function, thereby contributing to tumor suppression in TP53-mutated cancer.
Mesh Terms:
Activating Transcription Factor 3, Carcinogenesis, Cell Line, Tumor, Cell Movement, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Mutant Proteins, Mutation, NF-kappa B p52 Subunit, Neoplasm Invasiveness, Neoplasm Metastasis, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Activating Transcription Factor 3, Carcinogenesis, Cell Line, Tumor, Cell Movement, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Mutant Proteins, Mutation, NF-kappa B p52 Subunit, Neoplasm Invasiveness, Neoplasm Metastasis, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
J. Biol. Chem.
Date: Mar. 28, 2014
PubMed ID: 24554706
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