Id3 modulates cellular localization of bHLH Ptf1-p48 protein.

Abstract : Ptf1-p48 is a pancreas-specific bHLH transcriptional protein, which, in the normal adult pancreas, shows a restricted expression in acinar cells where it is predominantly localized in the nucleus and activates the transcription of exocrine-specific genes. Ptf1-p48 partners with two proteins to form the PTF1 active complex: a bHLH E-protein and suppressor of hairless RBP-J. Cytoplasmic mislocalization of Ptf1-p48 has been reported in pancreatic pathologies, suggesting its contribution in the early steps of pancreatic carcinogenesis. The aim of the our work was to elucidate the mechanisms regulating Ptf1-p48 subcellular localization. We hypothesized a role of Id proteins acting in a dominant-negative fashion by heterodimerizing with bHLH proteins. We reproduced Ptf1-p48 cytoplasmic mislocalization in acinar AR4-2J cells and demonstrated that a proliferative signal elicited by gastrin leads to increases in Id3 protein expression and levels of Id3/E47 and Id3/Ptf1-p48 interactions, and a decrease in the level of E47/Ptf1-p48 interaction. By contrast, Id3 silencing reversed the cytoplasmic mislocalization of Ptf1-p48 induced by gastrin. As E47 is responsible for the nuclear import of the PTF1 complex, disruption of this complex via Id3 interactions with both E47 and Ptf1-p48 appears to induce cytoplasmic mislocalization of Ptf1-p48. We then found that Ptf1-p48 is either absent or mislocalized in the cytoplasm and Id3 is overexpressed in human and murine pancreatic preneoplastic lesions. Our data provide novel insight into the regulation of Ptf1-p48 function and provide evidence that Ptf1-p48 cytoplasmic mislocalization and Id3 overexpression are early events in pancreatic cancer progression.
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Article dans une revue
International Journal of Cancer, Wiley, 2011, 129 (2), pp.295-306. 〈10.1002/ijc.25668〉
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Contributeur : Marie Francoise Simon <>
Soumis le : vendredi 5 août 2011 - 15:09:59
Dernière modification le : jeudi 13 septembre 2018 - 10:26:05

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Marlène Dufresne, Pascal Clerc, Madieng Dieng, Anissa Edir, Anne Couvelard, et al.. Id3 modulates cellular localization of bHLH Ptf1-p48 protein.. International Journal of Cancer, Wiley, 2011, 129 (2), pp.295-306. 〈10.1002/ijc.25668〉. 〈inserm-00613666〉



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