Cancers arise when cells escape normal controls on proliferation through activation of oncogenes and also bypass fail-safe barriers imposed by tumor suppressors that normally cause apoptosis or growth arrest (senescence) of pre-malignant cells. Proto-oncogenes encoding Ras GTPases are frequently activated in cancer cells, while components of the p53 or RB tumor suppressor pathways are disrupted in nearly all tumors. Elucidating the fundamental components of these oncogenic and anti-oncogenic pathways is essential for understanding how cancers develop and to identify unique vulnerabilities of tumor cells that can be exploited for therapeutic advantage. Our laboratory studies the C/EBP (CCAAT/enhancer binding protein) family of bZIP transcription factors, with particular emphasis on their involvement in cell proliferation and tumorigenesis. Our current research focuses on the functions and regulation of C/EBPbeta as a downstream effector of Ras and its role in tumor cells. Recent work from our laboratory also implicates C/EBPbeta in oncogene-induced senescence of primary fibroblasts, where it acts to restrain proliferation of cells expressing activated Ras by a mechanism requiring RB:E2F. C/EBPbeta may therefore possess both pro- and anti-tumorigenic properties. We seek to understand these opposing functions of C/EBPbeta in more mechanistic detail and to illuminate their contributions to cancer development in vivo.Post-translational regulation of C/EBPbeta activity: The DNA-binding activity of C/EBPbeta is intrinsically repressed and is activated in cells expressing oncogenic Ras or stimulated with growth factors. C/EBPbeta auto-inhibition requires at least three regions in the N-terminal half of the protein that are predicted to form secondary structure. We have mapped Ras-induced sites of phosphorylation on C/EBPbeta and identified a RSK kinase site in the leucine zipper as an important regulator of C/EBPbeta DNA-binding activity and dimerization. We are continuing to investigate how phosphorylation and other modifications such as lysine acetylation control C/EBPbeta DNA-binding, dimerization, and transcriptional activity and how such modifications affect its biological and oncogenic properties.C/EBPbeta and tumorigenesis: Work from our laboratory and others has revealed a critical role for C/EBPbeta in the development of certain cancers. C/EBPbeta-deficient mice were shown to be completely resistant to skin tumors induced by carcinogens that cause Ras mutations. C/EBPbeta is also essential for Myc/Raf-induced transformation of monocyte/macrophages and is required for these cells to evade apoptosis in the absence of extrinsic growth factors, a hallmark of leukemias and other tumor cells. We identified the IGF-I gene as a transcriptional target of C/EBPbeta in transformed macrophages and demonstrated that the survival defect of C/EBPbeta null cells stems from impaired autocrine signaling by IGF-I. To determine whether C/EBPbeta affects other kinds of tumors, we are investigating the effect of C/EBPbeta deficiency on carcinogen-induced cancers. Preliminary results indicate that C/EBPbeta KO mice exposed to ENU fail to develop lymphomas and show reduced incidence or malignancy of many other cancers. To extend these findings we are currently intercrossing C/EBPbeta KO mice with transgenic strains that develop tumors in specific tissues. We are also examining the expression and function of C/EBPbeta in human tumor cell lines to extend our findings to human malignancies.Role of C/EBPbeta in cellular senescence: In many primary (non-immortalized) cells, elevated levels of activated Ras or other oncogenes induce senescence, a stable form of cell cycle arrest that requires induction of the ARF-p53 and p16Ink4a-RB tumor suppressor pathways. Recent work indicates that oncogene-induced senescence (OIS) serves as a tumor surveillance mechanism in vivo.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Staiger, Jennifer; Lueben, Mary J; Berrigan, David et al. (2009) C/EBPbeta regulates body composition, energy balance-related hormones and tumor growth. Carcinogenesis 30:832-40
Spooner, Chauncey J; Sebastian, Thomas; Shuman, Jon D et al. (2007) C/EBPbeta serine 64, a phosphoacceptor site, has a critical role in LPS-induced IL-6 and MCP-1 transcription. Cytokine 37:119-27
Loomis, Kari D; Zhu, Songyun; Yoon, Kyungsil et al. (2007) Genetic ablation of CCAAT/enhancer binding protein alpha in epidermis reveals its role in suppression of epithelial tumorigenesis. Cancer Res 67:6768-76
Spooner, Chauncey J; Guo, Xiangrong; Johnson, Peter F et al. (2007) Differential roles of C/EBP beta regulatory domains in specifying MCP-1 and IL-6 transcription. Mol Immunol 44:1384-92
Lopez, Alex B; Wang, Chuanping; Huang, Charlie C et al. (2007) A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation. Biochem J 402:163-73
Suh, Hyung Chan; Gooya, John; Renn, Katie et al. (2006) C/EBPalpha determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood 107:4308-16
Mantena, Srinivasa Raju; Kannan, Athilakshmi; Cheon, Yong-Pil et al. (2006) C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc Natl Acad Sci U S A 103:1870-5
Sebastian, Thomas; Johnson, Peter F (2006) Stop and go: anti-proliferative and mitogenic functions of the transcription factor C/EBPbeta. Cell Cycle 5:953-7
Johnson, Peter F (2005) Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci 118:2545-55
Roy, Sanjit K; Shuman, Jon D; Platanias, Leonidas C et al. (2005) A role for mixed lineage kinases in regulating transcription factor CCAAT/enhancer-binding protein-{beta}-dependent gene expression in response to interferon-{gamma}. J Biol Chem 280:24462-71

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