This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rubinstein, M. Articles by Werner, H. Search for Related Content PubMed PubMed Citation Articles by Rubinstein, M. Articles by Werner, H. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene

Transcriptional Activation of the Insulin-Like Growth Factor I Receptor Gene by the Kruppel-Like Factor 6 (KLF6) Tumor Suppressor Protein: Potential Interactions between KLF6 and p53

Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University (M.R., G.I., H.W.), Tel Aviv 69978, Israel; Department of Medicine, University of Washington (S.R.P.), Seattle, Washington 98195; and Division of Liver Diseases, Mount Sinai School of Medicine (G.N., S.L.F.), New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Haim Werner, Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: hwerner{at}post.tau.ac.il.

The IGF system plays an important role in prostate cancer initiation and progression. Most of the biological actions of IGF-I and IGF-II are mediated by activation of the IGF-I receptor (IGF-IR). Evidence accumulated in recent years indicates that acquisition of the malignant phenotype is initially IGF-IR dependent, but progression toward metastatic stages is usually associated with a decrease in IGF-IR levels. The Kruppel-like factor 6 (KLF6) is a zinc finger-containing transcription factor that was shown to be mutated in a significant portion of prostate and other types of cancer. To examine the potential regulation of IGF-IR gene expression by KLF6, we measured KLF6 levels in prostate-derived cell lines displaying different levels of IGF-IR. The results of Western analysis showed that KLF6 levels were higher in nontumorigenic P69 cells expressing high IGF-IR levels than in metastatic M12 cells containing reduced IGF-IR levels. Transient coexpression of wild-type, but not mutated, KLF6 together with an IGF-IR promoter-luciferase reporter plasmid resulted in an approximately 3.4-fold stimulation of IGF-IR promoter activity. Furthermore, KLF6 expression induced a significant increment in endogenous IGF-IR levels. Deletion analysis of the IGF-IR promoter revealed that a cluster of four GC boxes located between nucleotides –399 and –331 mediates a significant portion of the transactivating effect of KLF6. KLF6, although unable to stimulate IGF-IR promoter activity in Sp1-null Drosophila-derived Schneider cells, significantly enhanced the effect of Sp1. To assess the potential interactions between KLF6 and p53 in the regulation of IGF-IR gene expression, transfections were performed in the colorectal cancer cell line HCT116^+/+, which expresses p53, and its HCT116^–/– derivative, which lacks p53. KLF6 exhibited an enhanced activity in p53-containing, compared with p53-null, cells. In addition, we were able to detect a physical interaction between KLF6 and p53. In summary, we have identified the IGF-IR gene as a novel downstream target for transcription factor KLF6. The regulation of IGF-IR gene expression by KLF6 may have significant implications in terms of cancer initiation and/or progression.

This article has been cited by other articles:

				I. Bentov, G. Narla, H. Schayek, K. Akita, S. R. Plymate, D. LeRoith, S. L. Friedman, and H. Werner Insulin-Like Growth Factor-I Regulates Kruppel-Like Factor-6 Gene Expression in a p53-Dependent Manner Endocrinology, April 1, 2008; 149(4): 1890 - 1897. [Abstract] [Full Text] [PDF]

				X. Wei, H. Xu, and D. Kufe Human Mucin 1 Oncoprotein Represses Transcription of the p53 Tumor Suppressor Gene Cancer Res., February 15, 2007; 67(4): 1853 - 1858. [Abstract] [Full Text] [PDF]

				N. Zhu, L. Gu, H. W. Findley, C. Chen, J.-T. Dong, L. Yang, and M. Zhou KLF5 Interacts with p53 in Regulating Survivin Expression in Acute Lymphoblastic Leukemia J. Biol. Chem., May 26, 2006; 281(21): 14711 - 14718. [Abstract] [Full Text] [PDF]

				F. Chiambaretta, H. Nakamura, F. De Graeve, H. Sakai, G. Marceau, Y. Maruyama, D. Rigal, B. Dastugue, J. Sugar, B. Y. J. T. Yue, et al. Kruppel-like Factor 6 (KLF6) Affects the Promoter Activity of the {alpha}1-Proteinase Inhibitor Gene Invest. Ophthalmol. Vis. Sci., February 1, 2006; 47(2): 582 - 590. [Abstract] [Full Text] [PDF]

				G. Narla, A. DiFeo, S. Yao, A. Banno, E. Hod, H. L. Reeves, R. F. Qiao, O. Camacho-Vanegas, A. Levine, A. Kirschenbaum, et al. Targeted Inhibition of the KLF6 Splice Variant, KLF6 SV1, Suppresses Prostate Cancer Cell Growth and Spread Cancer Res., July 1, 2005; 65(13): 5761 - 5768. [Abstract] [Full Text] [PDF]