Crosstalk between oncoprotein Ski and TGF-B signaling

癌蛋白 Ski 和 TGF-B 信号传导之间的串扰

• 批准号: 7169853
• 负责人: YIN SUN
• 金额: $ 24.49万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-05 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169853
• 关键词: Acetylation; Address; Apoptosis; Binding; Biological; Birds; CDKN1A gene; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cells; Complex; Contact Inhibition; DNA Binding; Data; Down-Regulation; E1A-associated p300 protein; EP300 gene; Embryo; Epithelial; Epithelial Cells; Event; Family; Fibroblasts; Gene Targeting; Genetic Transcription; Growth; Hematopoietic; Human; In Vitro; Lead; Link; Lung; Lysine; MCF7 cell; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Mink; Modification; Molecular; Mus; Muscle; Mutation; Myosin Heavy Chains; N-terminal; Nuclear; Nuclear Protein; Nuclear Proteins; Oncogene Activation; Oncogene Proteins; Pathway interactions; Physiological; Physiological Processes; Play; Protein Overexpression; Proteins; Proto-Oncogenes; Quail; RNA Interference; Regulation; Repression; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skiing; Testing; Thyroid Hormone Receptor; Transcription Repressor/Corepressor; Transcriptional Activation; Transducers; Transforming Growth Factor beta; Tumor Suppressor Proteins; cell growth; gene repression; human NCOR1 protein; inhibitor/antagonist; oncoprotein p21; promoter; response; tumorigenesis

DESCRIPTION (provided by applicant): Ski belongs to a family of protooncoproteins that transform avian embryo fibroblasts upon overexpression. It is a nuclear protein capable of activating or repressing gene transcription in a context dependent manner. We have shown that Ski can interact with Smad3, an intracellular mediator of transforming growth factor Beta (TGF-Beta) signaling. TGF-Beta potently blocks cellular proliferation; thus components of TGF-Beta signaling are candidates of tumor suppressors. Inactivation of TGF-Beta signal transducers through mutations or activation of oncogenes occurs as a frequent event in the genesis of human cancer. We have found that in response to TGF-Beta signaling, Ski forms a complex with Samd3/4. The resultant protein complex does not impede Smad's DNA binding, however blocks transcription mediated by Smads through recruitment of transcription corepressors. Epithelial cells overexpressing Ski are resistant to growth inhibition by TGF-B, which potentially implicates Ski's mechanism of transformation. More recently, we have found that overexpression of Ski in mammalian cells can lead to impaired regulation of cell cycle and proliferation. In addition, Ski appears to abrogate function of p300, another important tumor suppressor protein acting as an integrator of variety of cellular signaling pathways. Here we propose to determine the relationship between cell cycle and proliferation regulation by Ski and its ability to interact with Smad. We will also determine the molecular mechanisms underlying the regulation of p300 by Ski, and explore the role of Ski in cellular differentiation. These studies will lead to a better understanding of the cellular and molecular contexts for Ski's ability to regulate cell growth and differentiation as well as mechanisms of TGF-Beta signaling, and ultimately will help us to understand molecular mechanisms of tumorigenesis in general.

描述(申请人提供)：SKI属于原癌蛋白家族，在过度表达时转化为禽类胚胎成纤维细胞。它是一种核蛋白，能够以一种上下文相关的方式激活或抑制基因转录。我们已经证明Ski可以与Smad3相互作用，Smad3是转化生长因子β信号转导的细胞内介质。转化生长因子-β能有效地阻断细胞的增殖，因此转化生长因子-β信号的成分是肿瘤抑制的候选成分。癌基因突变或激活导致转化生长因子-β信号转导系统失活是人类癌症发生过程中的常见事件。我们发现，作为对转化生长因子-β信号的应答，Ski与Samd3/4形成了一个复合体。该复合体不会阻碍Smad的DNA结合，但会通过募集转录辅阻遏子来阻断Smads介导的转录。过度表达Ski的上皮细胞对转化生长因子-β的生长抑制具有抵抗力，这可能与Ski的转化机制有关。最近，我们发现Ski在哺乳动物细胞中的过度表达可以导致细胞周期和增殖调节的受损。此外，Ski似乎取消了p300的功能，p300是另一种重要的肿瘤抑制蛋白，发挥着多种细胞信号通路的整合作用。在这里，我们建议确定细胞周期和Ski的增殖调控之间的关系，以及它与Smad相互作用的能力。我们还将确定Ski调控p300的分子机制，并探索Ski在细胞分化中的作用。这些研究将有助于更好地了解Ski调控细胞生长和分化的细胞和分子背景以及转化生长因子-β信号转导机制，并最终帮助我们从总体上了解肿瘤发生的分子机制。