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Molecular and Cellular Biology, January 2009, p. 104-115, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01294-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Protein Kinase C{zeta} Represses the Interleukin-6 Promoter and Impairs Tumorigenesis In Vivo{triangledown} ,{dagger}

Anita S. Galvez,1,{ddagger} Angeles Duran,1,{ddagger} Juan F. Linares,1,{ddagger} Peterson Pathrose,1 Elias A. Castilla,1 Shadi Abu-Baker,1 Michael Leitges,2 Maria T. Diaz-Meco,1* and Jorge Moscat1*

Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, Ohio 45267,1 The Biotechnology Centre of Oslo, University of Oslo, N-0317, Oslo, Norway2

Received 14 August 2008/ Returned for modification 23 September 2008/ Accepted 21 October 2008

Gene alterations in tumor cells that confer the ability to grow under nutrient- and mitogen-deficient conditions constitute a competitive advantage that leads to more-aggressive forms of cancer. The atypical protein kinase C (PKC) isoform, PKC{zeta}, has been shown to interact with the signaling adapter p62, which is important for Ras-induced lung carcinogenesis. Here we show that PKC{zeta}-deficient mice display increased Ras-induced lung carcinogenesis, suggesting a new role for this kinase as a tumor suppressor in vivo. We also show that Ras-transformed PKC{zeta}-deficient lungs and embryo fibroblasts produced more interleukin-6 (IL-6), which we demonstrate here plays an essential role in the ability of Ras-transformed cells to grow under nutrient-deprived conditions in vitro and in a mouse xenograft system in vivo. We also show that PKC{zeta} represses histone acetylation at the C/EBPβ element in the IL-6 promoter. Therefore, PKC{zeta}, by controlling the production of IL-6, is a critical signaling molecule in tumorigenesis.

* Corresponding author. Mailing address: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267. Phone: (513) 558-8419. Fax: (513) 558-4454. E-mail for Jorge Moscat: jorge.moscat{at}uc.edu. E-mail for Maria Diaz-Meco: maria.diazmeco{at}uc.edu

{triangledown} Published ahead of print on 27 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Equal contribution.

Molecular and Cellular Biology, January 2009, p. 104-115, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01294-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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