title: Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis.
abstract: Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β 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 Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β 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-β signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore- 560012, India.
authors.forename: Ila
authors.initials: I
authors.lastname: Pant
authors.affiliation: Department of Oral and Maxillofacial Surgery D.A Pandu Memorial- R.V Dental College and Hospital, Bangalore-560078, India.
authors.forename: S Girish
authors.initials: SG
authors.lastname: Rao
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore- 560012, India.
authors.forename: Paturu
authors.initials: P
authors.lastname: Kondaiah
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D001114:Areca / Q000737:chemistry*; D002461:Cell Line, Transformed; D005260:Female; D005355:Fibrosis; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009754:Nuts / Q000737:chemistry*; D016759:Oncogene Protein p65(gag-jun) / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011230:Precancerous Conditions / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D016759:Oncogene Protein p65(gag-jun); D010936:Plant Extracts; D016212:Transforming Growth Factor beta; D048670:MAP Kinase Kinase 4