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OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-\u03b2 activation and its effects contributing to OSF. However, the mechanism for activation of TGF-\u03b2 signaling in OSF is still unknown. In this study we demonstrate activation of TGF-\u03b2 signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca<jats:sup>2+<\/jats:sup>\/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2\/c-Jun transcription factors resulted in TGF-\u03b2 transcription and its signaling. pATF2\/p-c-Jun were enriched on TGF-\u03b2 promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-\u03b2 signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.<\/jats:p>","DOI":"10.1038\/srep34314","type":"journal-article","created":{"date-parts":[[2016,10,6]],"date-time":"2016-10-06T10:02:36Z","timestamp":1475748156000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Role of areca nut induced JNK\/ATF2\/Jun axis in the activation of TGF-\u03b2 pathway in precancerous Oral Submucous Fibrosis"],"prefix":"10.1038","volume":"6","author":[{"given":"Ila","family":"Pant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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