Protein Kinase C (cid:2) Represses the Interleukin-6 Promoter and Impairs Tumorigenesis In Vivo (cid:1) †

ABSTRACT 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, PKCζ, has been shown to interact with the signaling adapter p62, which is important for Ras-induced lung carcinogenesis. Here we show that PKCζ-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 PKCζ-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 PKCζ represses histone acetylation at the C/EBPβ element in the IL-6 promoter. Therefore, PKCζ, by controlling the production of IL-6, is a critical signaling molecule in tumorigenesis.

[1]  D. Peeper,et al.  Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network , 2008, Cell.

[2]  T. Lawrence,et al.  “Re-educating” tumor-associated macrophages by targeting NF-κB , 2008, The Journal of experimental medicine.

[3]  J. Flores,et al.  The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. , 2008, Cancer cell.

[4]  S. Ghosh,et al.  Shared Principles in NF-κB Signaling , 2008, Cell.

[5]  M. Karin,et al.  Autocrine IL-6 signaling: a key event in tumorigenesis? , 2008, Cancer cell.

[6]  D. Santini,et al.  IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. , 2007, The Journal of clinical investigation.

[7]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[8]  K. Lim,et al.  Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. , 2007, Genes & development.

[9]  Michael Karin,et al.  References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S6 Tables S1 to S4 Gender Disparity in Liver Cancer Due to Sex Differences in Myd88-dependent Il-6 Production , 2022 .

[10]  M. Diaz-Meco,et al.  Signal integration and diversification through the p62 scaffold protein. , 2007, Trends in biochemical sciences.

[11]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[12]  T. Yamasaki,et al.  Requirement of androgen-dependent activation of protein kinase Czeta for androgen-dependent cell proliferation in LNCaP Cells and its roles in transition to androgen-independent cells. , 2006, Molecular endocrinology.

[13]  M. Diaz-Meco,et al.  Cell signaling and function organized by PB1 domain interactions. , 2006, Molecular cell.

[14]  M. Diaz-Meco,et al.  PKCζ at the crossroad of NF-κB and Jak1/Stat6 signaling pathways , 2006, Cell Death and Differentiation.

[15]  M. Diaz-Meco,et al.  PKCzeta at the crossroad of NF-kappaB and Jak1/Stat6 signaling pathways. , 2006, Cell death and differentiation.

[16]  M. Diaz-Meco,et al.  The p62 Scaffold Regulates Nerve Growth Factor-induced NF-κB Activation by Influencing TRAF6 Polyubiquitination* , 2005, Journal of Biological Chemistry.

[17]  A. Berns,et al.  Mouse models for human lung cancer. , 2005, Genes & development.

[18]  A. Mantovani,et al.  Smoldering and polarized inflammation in the initiation and promotion of malignant disease. , 2005, Cancer cell.

[19]  Richard A Flavell,et al.  Instruction of Distinct CD4 T Helper Cell Fates by Different Notch Ligands on Antigen-Presenting Cells , 2004, Cell.

[20]  R. DePinho,et al.  Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. , 2004, Cancer cell.

[21]  Manuel Serrano,et al.  The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. , 2004, Developmental cell.

[22]  J. Pollard.  Tumour-educated macrophages promote tumour progression and metastasis , 2004, Nature Reviews Cancer.

[23]  A. Durán,et al.  Essential role of RelA Ser311 phosphorylation by ζPKC in NF‐κB transcriptional activation , 2003 .

[24]  Manuel Serrano,et al.  Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. , 2003, Cancer cell.

[25]  M. Serrano,et al.  Genetic inactivation of Par4 results in hyperactivation of NF‐κB and impairment of JNK and p38 , 2003, EMBO reports.

[26]  A. Durán,et al.  Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. , 2003, The EMBO journal.

[27]  H. Varmus,et al.  Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. , 2001, Genes & development.

[28]  Juan F. García,et al.  Targeted Disruption of the ζPKC Gene Results in the Impairment of the NF-κB Pathway , 2001 .

[29]  A. Newton,et al.  The Carboxyl Terminus of Protein Kinase C Provides a Switch to Regulate Its Interaction with the Phosphoinositide-dependent Kinase, PDK-1* , 2001, The Journal of Biological Chemistry.

[30]  A. Durán,et al.  Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. , 2001, Molecular cell.

[31]  H. Nakano,et al.  The atypical PKC‐interacting protein p62 channels NF‐κB activation by the IL‐1–TRAF6 pathway , 2000, The EMBO journal.

[32]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[33]  M. Serrano,et al.  The downregulation of the pro‐apoptotic protein Par‐4 is critical for Ras‐induced survival and tumor progression , 1999, The EMBO journal.

[34]  C. Y. Wang,et al.  Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. , 1997, Science.

[35]  L. Sanz,et al.  Evidence for the in vitro and in vivo interaction of Ras with protein kinase C zeta. , 1994, The Journal of biological chemistry.

[36]  M. Diaz-Meco,et al.  Protein kinase C ζ isoform is critical for mitogenic signal transduction , 1993, Cell.

[37]  M. Diaz-Meco,et al.  Protein kinase C zeta isoform is critical for mitogenic signal transduction. , 1993, Cell.

[38]  A. Malkinson.  Promoters, co-carcinogens and inhibitors of pulmonary carcinogenesis in mice: an overview. , 1991, Experimental lung research.

[39]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.