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Plos Genetics : Inactivation of Tif1C Cooperates with Krasg12D to Induce Cystic Tumors of the Pancreas, Volume 5

By Clurman, Bruce E.

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Book Id: WPLBN0003927792
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Reproduction Date: 2015

Title: Plos Genetics : Inactivation of Tif1C Cooperates with Krasg12D to Induce Cystic Tumors of the Pancreas, Volume 5  
Author: Clurman, Bruce E.
Volume: Volume 5
Language: English
Subject: Journals, Science, Genetics
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Genetics
Historic
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Publisher: Plos

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Clurman, B. E. (n.d.). Plos Genetics : Inactivation of Tif1C Cooperates with Krasg12D to Induce Cystic Tumors of the Pancreas, Volume 5. Retrieved from http://www.nationalpubliclibrary.com/


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Description : Inactivation of the Transforming Growth Factor Beta (TGFb) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1c) has recently been proposed to be involved in TGFb signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1c in pancreatic carcinogenesis. Using conditional Tif1c knockout mice (Tif1clox/lox), we selectively abrogated Tif1c expression in the pancreas of Pdx1-Cre:Tif1clox/lox mice. We also generated Pdx1-Cre:LSL-KrasG12D:Tif1clox/lox mice to address the effect of Tif1c loss-of-function in precancerous lesions induced by oncogenic KrasG12D. Finally, we analyzed TIF1c expression in human pancreatic tumors. In our mouse model, we showed that Tif1c was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre:LSL-KrasG12D:Smad4lox/lox mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1c don’t have strictly redundant functions. Finally, we report that TIF1c expression is markedly downregulated in human pancreatic tumors by quantitative RT–PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1c is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1c in the multifaceted functions of TGFb in carcinogenesis and development.

 

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