title: The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins.
abstract: 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.
authors.affiliation: From the Center for Cell Biology and Cancer Research and.
authors.forename: Saisai
authors.initials: S
authors.lastname: Wei
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.forename: Chunwan
authors.initials: C
authors.lastname: Lu
authors.forename: Sarah
authors.initials: S
authors.lastname: Malmut
authors.forename: Jianqiao
authors.initials: J
authors.lastname: Zhang
authors.forename: Shumei
authors.initials: S
authors.lastname: Ren
authors.forename: Guohua
authors.initials: G
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Dale D
authors.initials: DD
authors.lastname: Tang
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D050505:Mutant Proteins; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: ATF3; Drug Resistance; Invasion; Lung Cancer; Migration; Mutant p53; p53