Id3 modulates cellular localization of bHLH Ptf1-p48 protein.
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.
Dufresne
Marlène
M
Inserm U858, F-31432 Toulouse, France.
Clerc
Pascal
P
Dieng
Madieng
M
Edir
Anissa
A
Couvelard
Anne
A
Delisle
Marie-Bernadette
MB
Fourmy
Daniel
D
Gigoux
Véronique
V
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism / Q000502:physiology*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D021381:Protein Transport; D011817:Rabbits; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D051796:Inhibitor of Differentiation Proteins; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D009363:Neoplasm Proteins; D014157:Transcription Factors; C494228:Isgf3g protein, mouse; C062602:transcription factor PTF1; C067679:Idb3 protein, mouse; C075640:ID3 protein, human