دورية أكاديمية
أعرض في EDS

Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia.

التفاصيل البيبلوغرافية
العنوان: Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia.
المؤلفون: Shi G; Department of Biological Sciences and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907-2064, USA., DiRenzo D, Qu C, Barney D, Miley D, Konieczny SF
المصدر: Oncogene [Oncogene] 2013 Apr 11; Vol. 32 (15), pp. 1950-8. Date of Electronic Publication: 2012 Jun 04.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
مواضيع طبية MeSH: Acinar Cells/*physiology , Basic Helix-Loop-Helix Transcription Factors/*metabolism , Carcinoma, Pancreatic Ductal/*genetics , Carcinoma, Pancreatic Ductal/*pathology , Metaplasia/*metabolism , Pancreatic Neoplasms/*genetics , Pancreatic Neoplasms/*pathology , Proto-Oncogene Proteins p21(ras)/*metabolism, Animals ; Carcinoma in Situ/genetics ; Carcinoma in Situ/metabolism ; Cell Line ; Cell Transformation, Neoplastic ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Metaplasia/pathology ; Mice ; Mice, Transgenic ; Pancreatic Ducts/pathology ; Pancreatic Neoplasms/metabolism ; Precancerous Conditions/genetics ; Precancerous Conditions/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Signal Transduction ; raf Kinases/metabolism
مستخلص: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers owing to a number of characteristics including difficulty in establishing early diagnosis and the absence of effective therapeutic regimens. A large number of genetic alterations have been ascribed to PDAC with mutations in the KRAS2 proto-oncogene thought to be an early event in the progression of disease. Recent lineage-tracing studies have shown that acinar cells expressing mutant Kras(G12D) are induced to transdifferentiate, generating duct-like cells through a process known as acinar-ductal metaplasia (ADM). ADM lesions then convert to precancerous pancreatic intraepithelial neoplasia (PanIN) that progresses to PDAC over time. Thus, understanding the earliest events involved in ADM/PanIN formation would provide much needed information on the molecular pathways that are instrumental in initiating this disease. As studying the transition of acinar cells to metaplastic ductal cells in vivo is complicated by analysis of the entire organ, an in vitro three dimensional (3D) culture system was used to model ADM outside the animal. Kras(G12D)-expressing acinar cells rapidly underwent ADM in 3D culture, forming ductal cysts that silenced acinar genes and activated duct genes, characteristics associated with in vivo ADM/PanIN lesions. Analysis of downstream KRAS signaling events established a critical importance for the Raf/MEK/ERK pathway in ADM induction. In addition, forced expression of the acinar-restricted transcription factor Mist1, which is critical to acinar cell organization, significantly attenuated Kras(G12D)-induced ADM/PanIN formation. These results suggest that maintaining MIST1 activity in Kras(G12D)-expressing acinar cells can partially mitigate the transformation activity of oncogenic KRAS. Future therapeutics that target both the MAPK pathway and Mist1 transcriptional networks may show promising efficacy in combating this deadly disease.
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معلومات مُعتمدة: R01 CA124586 United States CA NCI NIH HHS; R01 DK055489 United States DK NIDDK NIH HHS; CA124586 United States CA NCI NIH HHS; DK55489 United States DK NIDDK NIH HHS
المشرفين على المادة: 0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Bhlha15 protein, mouse)
EC 2.7.11.1 (raf Kinases)
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
EC 3.6.5.2 (Hras protein, mouse)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
تواريخ الأحداث: Date Created: 20120606 Date Completed: 20130619 Latest Revision: 20211021
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC3435479
DOI: 10.1038/onc.2012.210
PMID: 22665051
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5594
DOI:10.1038/onc.2012.210