Role of CEBP transcription factors in regulating cell gr

CEBP转录因子在调节细胞GR中的作用

• 批准号: 7291710
• 负责人: peter f johnson
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291710
• 关键词: Role; CEBP; transcription; factors; regulating; Role; CEBP; transcription; factors; regulating

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.

当细胞在增殖时逃脱正常的对照时，癌症通常是由于致癌基因的激活，并且要克服由肿瘤抑制子组成的失败安全屏障，其肿瘤抑制剂会引起诱导的肿瘤前细胞的细胞凋亡或生长停滞（衰老）。编码RAS GTPase的原始基因在癌细胞中经常被激活，而p53或RB肿瘤抑制途径的成分几乎总是在肿瘤中破坏。阐明这些致癌性和抗结构性途径的基本成分对于理解癌症如何发展和鉴定可用于治疗优势的肿瘤细胞的独特脆弱性至关重要。我们的实验室研究转录因子的C/EBP（CCAAT/增强子结合蛋白）家族，特别着重于它们参与细胞增殖和肿瘤发生。我们的研究目前侧重于C/EBPBETA作为RA的下游效应子的功能和调节，以及某些癌症中C/EBPBETA的要求。我们实验室的最新工作还揭示了C/EBPBETA在RAS诱导的原代成纤维细胞衰老中的作用，在这种情况下，它通过需要RB的机制来抑制细胞增殖：E2F。因此，C/EBPBETA可能具有促肿瘤和抗氧化型特性。我们试图以更机械的细节了解C/EBPBETA的这些相反功能，并阐明它们对体内癌症发展的贡献。 我们研究的主要重点是阐明C/EBPBETA在致癌性Ras或其下游效应激酶引起的细胞转化中的作用。 C/EBPBETA是一种广泛表达的核蛋白，在RAS信号传导后翻译后激活，这表明它可以用作通过RAS途径传播的致癌信号的核效应器。为了支持这一想法，我们先前表明C/EBPBETA缺陷的小鼠完全抵抗致癌物DMBA（与北卡罗来纳州立大学罗伯特·斯玛特（Robert Smart）和埃斯塔·斯特纳克（Esta Sterneck）的Robert Smart的合作项目所诱导的皮肤肿瘤的发展）。经过该方案的正常小鼠会形成表皮乳头状瘤，该乳头状瘤在RAS原癌基因中携带突变。因此，在实验动物模型中，C/EBPBETA对于皮肤肿瘤发生绝对必要。我们还发现，与野生型小鼠相比，癌症治疗后表皮中的C/EBPBETA无效动物在表皮中显示出更大的凋亡细胞，这表明C/EBPBETA参与抑制癌前细胞中编程的细胞死亡。由于C/EBPBETA活性受RAS信号的调节，因此我们假设C/EBPBETA是表皮角质形成细胞中RAS依赖性肿瘤发生途径的重要组成部分。我们目前正在研究使用小鼠癌变模型的其他癌症C/EBPBETA是否必不可少。我们的初步结果表明，C/EBPBETA非杀菌小鼠无法发展为ENU诱导的淋巴瘤，并且显示出许多其他癌症的发病率或恶性肿瘤。由于C/EBPBETA似乎在调节癌细胞的生长和存活中起着广泛的作用，因此该蛋白可能是开发新型抗肿瘤剂的有希望的靶标。 我们的实验室还发现，C/EBPBETA是巨噬细胞的肿瘤转化所必需的。与野生型细胞相比，C/EBPBETA - / - 被MYC/RAF表达逆转录病毒感染的骨髓衍生的巨噬细胞（J2）不显示生长因子独立性。在没有外源生长因子（“自给自足”）的情况下，生存的能力是许多白血病和其他癌症转化的标志。我们发现，J2转化的C/EBPBETA无脂细胞需要巨噬细胞粘合刺激因子（M-CSF）或类似的生存造血生长因子，而野生型细胞在无需外部因素的情况下避免了凋亡。