Functional analysis of the bHLH transcription factor Mist1 during pancreatic development and tumorigenesis
Abstract
Mist1 is a basic helix-loop-helix (bHLH) transcription factor that is specifically expressed in the exocrine cells of the pancreas, as well as in multiple other exocrine tissues including the prostate, salivary glands and mammary gland. Transgenic mice expressing a dominant-negative Mist1 Mutant Basic (Mist1MB) disorganized acinar structure, severe depletion of intercellular gap junctions, and activation of duct-specific genes, all of which suggest that alterations in the Mist1 bHLH network produces an acinar-to-ductal phenotypic switch in the pancreas. Since acinar-toductal metaplasia has been implicated in the development of pancreatic cancer, we generated a pancreatic cancer mouse model in which a mutated Kras oncogene (KrasG12D) was targeted into the Mist1 locus (Mist1KrasG12D/+ mice) to study Mist1 function during pancreatic tumorigenesis. Mist1KrasG12D/+ mice developed pancreatic cancer with 100% penetrance. Extensive acinar-to-ductal metaplasia was evident in Mist1KrasG12D/+ pancreata, whose morphological transition was tightly associated with Mist1 activity. Studies on Mist1KrasG12D/LacZ mice in which the Mist1 gene was completely deleted revealed an early death within three days after birth. Newborn Mist1KrasG12D/LacZ pancreata exhibited a severe structural distortion and an 85% cell proliferation index, transgene exhibited a which may account for the overall organ failure and animal death. A similar acceleration in pancreatic transformation was observed when the Mist1 gene was deleted in the LoxP-Stop-LoxP (LSL)-KrasG12D; p48Cre/+ pancreatic cancer mouse model, in which the KrasG12D oncogene was driven by the endogenous Kras promoter in a pancreas-specific manner. Mist1KO; LSL-KrasG12D; p48 Cre/+ mice have greatly enlarged pancreata at early ages when compared to Mist1WT; LSL-KrasG12D; p48Cre/+ mice. Pancreatic tumorigenesis in Mist1KO; LSL-Kras G12D; p48Cre/+ mice was significantly accelerated with an early appearance and broader distribution of the direct neoplastic precursors to human pancreatic ductal adenocarcinoma---pancreatic intraepithelial neoplasia (PanIN). In addition, a tight correlation between Mist1 gene activity and the molecular heterogeneity of PanIN lesions was noted in LSL-Kras G12D; p48Cre/+ mice. Our results suggest that Mist1 is important for maintaining the fully differentiated state of pancreatic acinar cells and for suppressing pancreatic tumorigenesis triggered by activating Kras mutations.
Degree
Ph.D.
Advisors
Konieczny, Purdue University.
Subject Area
Molecular biology
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