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Science 21 December 2001:
Vol. 294. no. 5551, pp. 2563 - 2566
DOI: 10.1126/science.1066326
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Reports

KLF6, a Candidate Tumor Suppressor Gene Mutated in Prostate Cancer

Goutham Narla,1 Karen E. Heath,2* Helen L. Reeves,1* Dan Li,1 Luciana E. Giono,1 Alec C. Kimmelman,3 Marc J. Glucksman,4dagger Jyothsna Narla,7 Francis J. Eng,1 Andrew M. Chan,3 Anna C. Ferrari,35 John A. Martignetti,236 Scott L. Friedman1ddagger

Kruppel-like factor 6 (KLF6) is a zinc finger transcription factor of unknown function. Here, we show that the KLF6 gene is mutated in a subset of human prostate cancer. Loss-of-heterozygosity analysis revealed that one KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirm that whereas wild-type KLF6 up-regulates p21 (WAF1/CIP1) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. Our data suggest that KLF6 is a tumor suppressor gene involved in human prostate cancer.

1 Division of Liver Diseases, Department of Medicine,
2 Department of Human Genetics,
3 The Derald H. Ruttenberg Cancer Center,
4 Department of Neurobiology,
5 Division of Medical Oncology, Department of Medicine, and
6 Department of Pediatrics, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 1170F, Box 1123, New York, NY, 10029, USA.
7 Regional Medical Center, 225 North Jackson, San Jose, CA, 95116, USA.
*   These authors contributed equally to this work.

dagger    Present address: Structural Neurobiology and Proteomics Laboratory, Department of Biochemistry and Molecular Biology, FUHS/Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.

ddagger    To whom correspondence should be addressed. E-mail: frieds02{at}doc.mssm.edu

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Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1.
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Identification of MoKA, a Novel F-Box Protein That Modulates Kruppel-Like Transcription Factor 7 Activity.
S. Smaldone, F. Laub, C. Else, C. Dragomir, and F. Ramirez (2004)
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Positive and Negative Regulation of the Cardiovascular Transcription Factor KLF5 by p300 and the Oncogenic Regulator SET through Interaction and Acetylation on the DNA-Binding Domain.
S. Miyamoto, T. Suzuki, S. Muto, K. Aizawa, A. Kimura, Y. Mizuno, T. Nagino, Y. Imai, N. Adachi, M. Horikoshi, et al. (2003)
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W.A. Schulz, M. Burchardt, and M.V. Cronauer (2003)
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Suppression of Prostate Tumor Growth by U19, a Novel Testosterone-regulated Apoptosis Inducer.
W. Xiao, Q. Zhang, F. Jiang, M. Pins, J. M. Kozlowski, and Z. Wang (2003)
Cancer Res. 63, 4698-4704
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Ectopic expression of Kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier.
J. Jaubert, J. Cheng, and J. A. Segre (2003)
Development 130, 2767-2777
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Transcriptional Activation of the Human Inducible Nitric-oxide Synthase Promoter by Kruppel-like Factor 6.
V. G. Warke, M. P. Nambiar, S. Krishnan, K. Tenbrock, D. A. Geller, N. P. Koritschoner, J. L. Atkins, D. L. Farber, and G. C. Tsokos (2003)
J. Biol. Chem. 278, 14812-14819
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Kruppel Cripples Prostate Cancer: KLF6 Progress and Prospects.
G. Narla, S. L. Friedman, and J. A. Martignetti (2003)
Am. J. Pathol. 162, 1047-1052
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Deletion, Mutation, and Loss of Expression of KLF6 in Human Prostate Cancer.
C. Chen, E.-R. Hyytinen, X. Sun, H. J. Helin, P. A. Koivisto, H. F. Frierson Jr, R. L. Vessella, and J.-T. Dong (2003)
Am. J. Pathol. 162, 1349-1354
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Allelic Loss of p53 Gene Is Associated with Genesis and Maintenance, but not Invasion, of Mouse Carcinoma in Situ of the Bladder.
J. Cheng, H. Huang, J. Pak, E. Shapiro, T.-T. Sun, C. Cordon-Cardo, F. M. Waldman, and X.-R. Wu (2003)
Cancer Res. 63, 179-185
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Multiple Genes in Human 20q13 Chromosomal Region Are Involved in an Advanced Prostate Cancer Xenograft.
A. Bar-Shira, J. H. Pinthus, U. Rozovsky, M. Goldstein, W. R. Sellers, Y. Yaron, Z. Eshhar, and A. Orr-Urtreger (2002)
Cancer Res. 62, 6803-6807
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Regulation of Corneal Keratin-12 Gene Expression by the Human Kruppel-like Transcription Factor 6.
F. Chiambaretta, L. Blanchon, B. Rabier, W. W.-Y. Kao, J. J. Liu, B. Dastugue, D. Rigal, and V. Sapin (2002)
Invest. Ophthalmol. Vis. Sci. 43, 3422-3429
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Science. ISSN 0036-8075 (print), 1095-9203 (online)