title: Regulation of KLF4 turnover reveals an unexpected tissue-specific role of pVHL in tumorigenesis.
abstract: The transcription factor Krüppel-like factor 4 (KLF4) is an important regulator of cell-fate decision, including cell-cycle regulation, apoptosis, and stem cell renewal, and plays an ambivalent role in tumorigenesis as a tissue-specific tumor suppressor or oncogene. Here, we report that the Von Hippel-Lindau gene product, pVHL, physically interacts with KLF4 and regulates its rapid turnover observed in both differentiated and stem cells. We provide mechanistic insights into KLF4 degradation and show that pVHL depletion in colorectal cancer cells leads to cell-cycle arrest concomitant with increased transcription of the KLF4-dependent p21 gene. Finally, immunohistochemical staining revealed elevated pVHL and reduced KLF4 levels in colon cancer tissues. We therefore propose that unexpectedly pVHL, via the degradation of KLF4, is a facilitating factor in colorectal tumorigenesis.
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Armin M
authors.initials: AM
authors.lastname: Gamper
authors.forename: Xinxian
authors.initials: X
authors.lastname: Qiao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kim
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Michelle C
authors.initials: MC
authors.lastname: DeSimone
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human