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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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https://www.hal.inserm.fr/inserm-00613666
Contributor : Marie Francoise Simon <>
Submitted on : Friday, August 5, 2011 - 3:09:59 PM
Last modification on : Wednesday, August 19, 2020 - 11:16:36 AM

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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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