Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-beta pathway in precancerous Oral Submucous Fibrosis

Pant, Ila and Rao, Girish S and Kondaiah, Paturu (2016) Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-beta pathway in precancerous Oral Submucous Fibrosis. In: SCIENTIFIC REPORTS, 6 .

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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-beta driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-beta activation and its effects contributing to OSF. However, the mechanism for activation of TGF-beta signaling in OSF is still unknown. In this study we demonstrate activation of TGF-beta 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-beta transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-beta 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-beta signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

Item Type:	Journal Article
Publication:	SCIENTIFIC REPORTS
Additional Information:	Copy right for this article belongs to the NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	03 Dec 2016 06:22
Last Modified:	03 Dec 2016 06:22
URI:	http://eprints.iisc.ac.in/id/eprint/55270

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