Regulation of KLF4 Turnover Reveals an Unexpected Tissue-Specific Role of pVHL in Tumorigenesis

被引：71

作者：

Gamper, Armin M. ^{[1
,2
]}

Qiao, Xinxian ^{[1
,2
]}

Kim, Jennifer ^{[3
]}

Zhang, Liyong ^{[1
,2
]}

DeSimone, Michelle C. ^{[4
]}

Rathmell, W. Kimryn ^{[4
]}

Wan, Yong ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Dept Cell Biol & Physiol, Sch Med, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA

[3] Carnegie Mellon Univ, Dept Biol, Pittsburgh, PA 15213 USA

[4] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

来源：

MOLECULAR CELL | 2012年 / 45卷 / 02期

基金：

美国国家卫生研究院;

关键词：

KRUPPEL-LIKE FACTOR-4; HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR; DNA-DAMAGE; CANCER; CELLS; KRUPPEL-LIKE-FACTOR-4; PROTEIN; GROWTH; MODELS;

D O I：

10.1016/j.molcel.2011.11.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The transcription factor Kruppel-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.

引用

页码：233 / 243

页数：11

共 26 条

[11] Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer [J].

Kaiser, Sergio ;

Park, Young-Kyu ;

Franklin, Jeffrey L. ;

Halberg, Richard B. ;

Yu, Ming ;

Jessen, Walter J. ;

Freudenberg, Johannes ;

Chen, Xiaodi ;

Haigis, Kevin ;

Jegga, Anil G. ;

Kong, Sue ;

Sakthivel, Bhuvaneswari ;

Xu, Huan ;

Reichling, Timothy ;

Azhar, Mohammad ;

Boivin, Gregory P. ;

Roberts, Reade B. ;

Bissahoyo, Anika C. ;

Gonzales, Fausto ;

Bloom, Greg C. ;

Eschrich, Steven ;

Carter, Scott L. ;

Aronow, Jeremy E. ;

Kleimeyer, John ;

Kleimeyer, Michael ;

Ramaswamy, Vivek ;

Settle, Stephen H. ;

Boone, Braden ;

Levy, Shawn ;

Graff, Jonathan M. ;

Doetschman, Thomas ;

Groden, Joanna ;

Dove, William F. ;

Threadgill, David W. ;

Yeatman, Timothy J. ;

Coffey, Robert J., Jr. ;

Aronow, Bruce J. .

GENOME BIOLOGY, 2007, 8 (07)

[12] Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach [J].

Katz, JP ;

Perreault, N ;

Goldstein, BG ;

Actman, L ;

McNally, SR ;

Silberg, DG ;

Furth, EE ;

Kaestner, KH .

GASTROENTEROLOGY, 2005, 128 (04) :935-945

[13] Decreased growth of Vhl-/- fibrosarcomas is associated with elevated levels of cyclin kinase inhibitors p21 and p27 [J].

Mack, FA ;

Patel, JH ;

Biju, MP ;

Haase, VH ;

Simon, AC .

MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (11) :4565-4578

[14] Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth [J].

Mack, FA ;

Rathmell, WK ;

Arsham, AM ;

Gnarra, J ;

Keith, B ;

Simon, MC .

CANCER CELL, 2003, 3 (01) :75-88

[15] The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis [J].

Maxwell, PH ;

Wiesener, MS ;

Chang, GW ;

Clifford, SC ;

Vaux, EC ;

Cockman, ME ;

Wykoff, CC ;

Pugh, CW ;

Maher, ER ;

Ratcliffe, PJ .

NATURE, 1999, 399 (6733) :271-275

[16] The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology [J].

McConnell, Beth B. ;

Ghaleb, Amr M. ;

Nandan, Mandayam O. ;

Yang, Vincent W. .

BIOESSAYS, 2007, 29 (06) :549-557

[17] Role of the VHL (von Hippel-Lindau) gene in renal cancer:: a multifunctional tumour suppressor [J].

Nyhan, Michelle J. ;

O'Sullivan, Gerald C. ;

McKenna, Sharon L. .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2008, 36 :472-478

[18] In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations [J].

Rathmell, WK ;

Hickey, MM ;

Bezman, NA ;

Chmielecki, CA ;

Carraway, NC ;

Simon, MC .

CANCER RESEARCH, 2004, 64 (23) :8595-8603

[19] KLF4, p21 and context-dependent opposing forces in cancer [J].

Rowland, BD ;

Peeper, DS .

NATURE REVIEWS CANCER, 2006, 6 (01) :11-23

[20] The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene [J].

Rowland, BD ;

Bernards, R ;

Peeper, DS .

NATURE CELL BIOLOGY, 2005, 7 (11) :1074-1082

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