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 exocrinespecific 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.Pancreatic cancer is a devastating disease with an overall 5-year survival of less than 5%. It is often not diagnosed until after the cancer has metastasized and therefore becomes very challenging to treat. During the last 10 years, the precursor lesions to invasive pancreatic cancer have been defined. 1 Pancreatic intraepithelial neoplasia (PanIN) are by far the most common of these lesions and are thought to initiate in the small ducts of the pancreas. PanIN have been validated by murine models that recapitulate the histologic progression hypothesized to occur in humans. These genetically engineered mouse models direct the endogenous expression of mutant KrasG12D to progenitor cells or acinar and centroacinar cells of the mouse pancreas. [2][3][4] Careful examination of the pathologic changes in these models suggests that, in addition to ductal cells, centroacinar cells and/or acinar cells can give rise to PanIN. 5 Lineage tracing studies with reporter mice confirmed that ductal elements can have an acinar histogenesis. They demonstrated that PanIN lesions are derivatives of differentiated acinar cells in response to chronic injury or when a mutant endogenous KrasG12D allele is expressed from its endogenous promoter in acinar cells. 3,4,6 In addition to these results from the mouse models, it has been demonstrated that acinar cel...

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“…Several factors may explain the different observations, including variations in analytical techniques (mRNA, protein, immunostaining methods). Our Id3 immunohistological results are in agreement with a recent study of Id3 and p48 in PDA (43). …”

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

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The Basic Helix-Loop-Helix Transcription Factor E47 Reprograms Human Pancreatic Cancer Cells to a Quiescent Acinar State With Reduced Tumorigenic Potential

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