Cancers arise when cells escape normal controls on proliferation, usually due to activation of oncogenes, and surmount fail-safe barriers consisting of tumor suppressors whose induction causes 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 almost invariably disrupted in 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 transcription factors, with particular emphasis on their involvement in cell proliferation and tumorigenesis. Our research currently focuses on the functions and regulation of C/EBPbeta as a downstream effector of Ras and the requirement for C/EBPbeta in certain cancers. Recent work from our laboratory has also revealed a role for C/EBPbeta in Ras-induced senescence of primary fibroblasts, where it acts to restrain cell proliferation by a mechanism requiring RB:E2F. Therefore, C/EBPbeta may 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.? ? A major focus of our research is to elucidate the role of C/EBPbeta in cellular transformation induced by oncogenic Ras or its downstream effector kinases. C/EBPbeta is a widely expressed nuclear protein that is post-translationally activated by Ras signaling, suggesting that it could serve as a nuclear effector of oncogenic signals transmitted via the Ras pathway. In support of this idea, we previously showed that C/EBPbeta-deficient mice are completely resistant to the development of skin tumors induced by the carcinogen, DMBA (a collaborative project with Robert Smart, North Carolina State University, and Esta Sterneck, NCI-Frederick). Normal mice subjected to this protocol develop epidermal papillomas that carry mutations in the Ras proto-oncogene. Thus, C/EBPbeta is absolutely essential for skin tumorigenesis in an experimental animal model. We also found that C/EBPbeta null animals display significantly greater numbers of apoptotic cells in the epidermis after carcinogen treatment compared to wild type mice, suggesting that C/EBPbeta is involved in suppressing programmed cell death in pre-cancerous cells. Since C/EBPbeta activity is regulated by Ras signaling, we hypothesize that C/EBPbeta is an essential component of the Ras-dependent tumorigenesis pathway in epidermal keratinocytes. We are currently investigating whether C/EBPbeta is essential for other cancers using mouse carcinogenesis models. Our preliminary results indicate that C/EBPbeta nullizygous mice fail to develop ENU-induced lymphomas and show reduced incidence or malignancy of many other cancers. Since C/EBPbeta appears to have a broad role in regulating growth and survival of cancer cells, this protein may be an promising target for the development of novel anti-tumorigenic agents.? ? Our laboratory has also found that C/EBPbeta is required for neoplastic transformation of macrophages. In contrast to wild-type cells, C/EBPbeta-/- bone marrow-derived macrophages infected with a Myc/Raf-expressing retrovirus (J2) do not display growth factor independence. The ability to survive in the absence of exogenous growth factors (""""""""self sufficiency"""""""") is a hallmark of transformation in many leukemias and other cancers. We found that J2-transformed, C/EBPbeta nullizygous cells require macrophage-colony stimulating factor (M-CSF) or similar hematopoietic growth factors for survival, whereas wild type cells evade apoptosis without a requirement for extrinsic factors.
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