Id3 modulates cellular localization of bHLH Ptf1‐p48 protein

• Published in: International journal of cancer Vol. 129; no. 2; pp. 295 - 306
• Main Authors: Dufresne, Marlène, Clerc, Pascal, Dieng, Madieng, Edir, Anissa, Couvelard, Anne, Delisle, Marie‐Bernadette, Fourmy, Daniel, Gigoux, Véronique
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.07.2011; Wiley-Blackwell; Wiley
• Subjects: acinar‐ductal metaplasia; Adenocarcinoma; Adenocarcinoma - metabolism; Animals; Basic Helix-Loop-Helix Transcription Factors; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biochemistry, Molecular Biology; Biological and medical sciences; Cytoplasm; Cytoplasm - metabolism; Disease Models, Animal; gastrin; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Id proteins; Inhibitor of Differentiation Proteins; Inhibitor of Differentiation Proteins - metabolism; Inhibitor of Differentiation Proteins - physiology; Interferon-Stimulated Gene Factor 3, gamma Subunit; Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism; Life Sciences; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Transgenic; Neoplasm Proteins; Neoplasm Proteins - metabolism; Neoplasm Proteins - physiology; pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - metabolism; preneoplastic lesions; Protein Transport; Ptf1‐p48; Rabbits; Rats; Transcription Factors; Transcription Factors - metabolism; Tumors; Premalignant lesion; acinar-ductal metaplasia; Malignant tumor; Protein; Id proteins; Metaplasia; Ptf1-p48; pancreatic cancer; Gastrointestinal hormone; Cancerology; Pancreas cancer; Gastrin; preneoplastic lesions; Digestive diseases; bHLH family; Localization; Cancer; Pancreatic disease; gastrin
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25668

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.