Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis.
Human Kruppel-like factor 2 (KLF2) is a Cys(2)/His(2) 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.
Wang
Fang
F
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Zhu
Yu
Y
Huang
Yan
Y
McAvoy
Sarah
S
Johnson
William B
WB
Cheung
Tak Hong
TH
Chung
Tony Kwok Hung
TK
Lo
Keith Wing Kit
KW
Yim
So Fan
SF
Yu
May M Y
MM
Ngan
Hextan Y S
HY
Wong
Yick Fu
YF
Smith
David I
DI
D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004249:DNA Damage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms; D010053:Ovary / Q000502:physiology; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D016335:Zinc Fingers
D018797:Cell Cycle Proteins; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human