Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis

Human Kruppel-like factor 2 (KLF2) is a Cys2/His2 zinc-finger-containing transcriptional factor, which is involved in multiple cellular pathways. Utilizing gene expression profiling to identify aberrantly expressed genes in ovarian cancer, we found that KLF2 was significantly and specifically downregulated in ovarian tumors. After reintroducing KLF2 into ovarian cancer cell lines, we observed decreased cell growth and increased sensitivity to DNA damage-induced apoptosis. Analysis of genes that could be potential targets of KLF2 revealed that KLF2 negatively regulated WEE1 expression. WEE1 encodes a tyrosine kinase that regulates the G2/M cell cycle transition. Expression of KLF2 markedly repressed the transcription of WEE1 by directly binding to an SP1/CPBP motif located between −252 bp and the start codon of the WEE1 promoter. Both activation and zinc-finger domains of KLF2 were required for this suppression of Wee1 expression. In addition, we demonstrated that Wee1 expression prevents cancer cells from undergoing apoptosis in response to DNA damage; however, this resistance was abolished by coexpression of KLF2, which inhibits WEE1 transcription. Thus, the level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis.

[1]  H. Frierson,et al.  Deletion, mutation, and loss of expression of KLF6 in human prostate cancer. , 2003, The American journal of pathology.

[2]  V. Yang,et al.  Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. , 2003, Journal of molecular biology.

[3]  J. Lingrel,et al.  KLF2 inhibits Jurkat T leukemia cell growth via upregulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 , 2004, Oncogene.

[4]  S. Friedman,et al.  KLF6, a Candidate Tumor Suppressor Gene Mutated in Prostate Cancer , 2001, Science.

[5]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[6]  M. Nibert,et al.  Comparisons of the M1 genome segments and encoded μ2 proteins of different reovirus isolates , 2004, Virology Journal.

[7]  K. Bland,et al.  Nuclear Localization of KLF4 Is Associated with an Aggressive Phenotype in Early-Stage Breast Cancer , 2004, Clinical Cancer Research.

[8]  P. D. de Groot,et al.  Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). , 2002, Blood.

[9]  S. Friedman,et al.  Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1 , 2004, Cancer Research.

[10]  F. Luscinskas,et al.  KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation , 2004, The Journal of experimental medicine.

[11]  S. Friedman,et al.  Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6 , 2004, Oncogene.

[12]  S. Friedman,et al.  Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. , 2004, Gastroenterology.

[13]  M. Yanagida,et al.  HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25. , 2001, Virology.

[14]  A. Pendergast,et al.  Nuclear tyrosine kinases: from Abl to WEE1. , 1996, Current opinion in cell biology.

[15]  S. Friedman,et al.  Frequent inactivation of the tumor suppressor Kruppel‐like factor 6 (KLF6) in hepatocellular carcinoma , 2004, Hepatology.

[16]  R. Rowley,et al.  The wee1 protein kinase is required for radiation-induced mitotic delay , 1992, Nature.

[17]  J. Bieker.  Krüppel-like Factors: Three Fingers in Many Pies* , 2001, Journal of Biological Chemistry.

[18]  M. Kamata,et al.  Increased Levels of Wee-1 Kinase in G2 Are Necessary for Vpr- and Gamma Irradiation-Induced G2 Arrest , 2004, Journal of Virology.

[19]  F. McKeon,et al.  Tyrosine kinases wee1 and mik1 as effectors of DNA replication checkpoint control. , 1996, Progress in cell cycle research.

[20]  David I. Smith,et al.  Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer* , 2003, Journal of Biological Chemistry.

[21]  J. Black,et al.  Sp1 and krüppel‐like factor family of transcription factors in cell growth regulation and cancer , 2001, Journal of cellular physiology.

[22]  Channing S. Mahatan,et al.  The Gut-enriched Krüppel-like Factor (Krüppel-like Factor 4) Mediates the Transactivating Effect of p53 on the p21 WAF1/Cip1 Promoter* , 2000, The Journal of Biological Chemistry.

[23]  V. Yang,et al.  Krüppel-like Factor 4 Mediates p53-dependent G1/S Cell Cycle Arrest in Response to DNA Damage* , 2003, The Journal of Biological Chemistry.

[24]  R. Kawahara,et al.  Regulation of the vav proto-oncogene by LKLF. , 2001, Gene.

[25]  C. T. Kuo,et al.  The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. , 1997, Genes & development.

[26]  V. Yang,et al.  Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer , 2004, Oncogene.

[27]  H. Hauner,et al.  The Krüppel-like Factor KLF2 Inhibits Peroxisome Proliferator-activated Receptor-γ Expression and Adipogenesis* , 2003, The Journal of Biological Chemistry.

[28]  J. Lingrel,et al.  Fluid shear stress induces endothelial KLF2 gene expression through a defined promoter region , 2004, Biological chemistry.

[29]  M. Korbonits,et al.  The Krüppel-like transcription factor 6 gene in sporadic pituitary tumours. , 2003, Endocrine-related cancer.

[30]  G. Ito,et al.  Krüppel-Like Factor 6 Is Frequently Down-Regulated and Induces Apoptosis in Non-Small Cell Lung Cancer Cells , 2004, Cancer Research.

[31]  T. Lawrence,et al.  Wild-Type TP53 Inhibits G2-Phase Checkpoint Abrogation and Radiosensitization Induced by PD0166285, a WEE1 Kinase Inhibitor , 2002, Radiation research.