FUNCTIONAL ANALYSIS OF SMAF1, AN OBESITY CANDIDATE GENE

肥胖候选基因 SMAF1 的功能分析

• 批准号: 6709231
• 负责人: CYNTHIA M SMAS
• 金额: $ 14.7万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709231
• 关键词: adipocytes; biological signal transduction; cell differentiation; gene expression; gene mutation; genetic promoter element; genetic regulation; genetic transcription; hormone receptor; immunoprecipitation; luciferin monooxygenase; microarray technology; obesity; peroxisome proliferator activated receptor; protein protein interaction; protein structure function; reporter genes; tissue /cell culture; tumor necrosis factor alpha; yeast two hybrid system

DESCRIPTION (provided by applicant): Obesity is on the rise in the United States where it affects one-third of the population. The impact of increased adipose mass on human health is wide-ranging with increased risk of cardiovascular disease, diabetes and some forms of cancer. Studies in human lipodystrophy and in mouse models have demonstrated that a dearth of adipose tissue also carries health risks, most notably diabetes. To achieve and maintain optimal health, the genes that impact this balance between health and disease in adipose tissue must be identified and their mechanisms of function determined. Recent DNA microarray studies have revealed that in addition to the long-standing role of PPARgamma and C/EBP proteins in adipose biology, a variety of other genes are modulated during adipogenesis. A central principle that has been highly productive in defining details of adipogenesis is the study of those genes showing specific and unique patterns of expression in adipose tissue; they are most likely to offer key molecular insights unique to adipose tissue regulation. We have recently cloned a novel adipocyte-specific gene, small activating factor -SMAF1. SMAF1 is enriched in murine intra-abdominal WAT tissue compared with subcutaneous WAT. Furthermore, SMAF1 shows differential regulation in obesity and by hormones and cytokines central to adipose physiology. The SMAF1 gene maps to a chromosomal region containing a novel obesity quantitative trait locus. SMAF1 transcript encodes a wholly novel molecule of 80 amino acids. SMAF1 does not belong to any type of known protein family but possesses a canonical nuclear hormone receptor LXXLL interaction motif. Preliminary data indicate that when fused to a Gal4 DNA binding domain SMAF1 is a strong transcriptional activator and that SMAF1 can potentiate PPAR?-mediated transcriptional signals. It is proposed that SMAF1 has a key role in adipose biology. The role of SMAF1 in adipocyte signaling, differentiation and function will be determined in this R21 application through three specific aims: 1.) The impact of ectopic SMAF1 in the 3T3-L1 in vitro model of adipogenesis; 2.) The impact of SMAF1 on PPARgamma transcriptional signals; and 3.) Identification of SMAF1 binding partners.

描述（由申请人提供）：肥胖在美国呈上升趋势，影响了三分之一的人口。脂肪量增加对人类健康的影响是广泛的，增加了患心血管疾病、糖尿病和某些癌症的风险。对人类脂肪营养不良和小鼠模型的研究表明，脂肪组织缺乏也会带来健康风险，最明显的是糖尿病。为了实现和维持最佳健康，必须确定脂肪组织中影响健康和疾病之间平衡的基因，并确定其功能机制。最近的DNA微阵列研究表明，除了PPARgamma和C/EBP蛋白在脂肪生物学中的长期作用外，多种其他基因在脂肪形成过程中也受到调节。在定义脂肪形成的细节方面，一个非常有成效的中心原则是研究那些在脂肪组织中表现出特定和独特表达模式的基因；它们最有可能为脂肪组织调节提供独特的关键分子见解。我们最近克隆了一个新的脂肪细胞特异性基因，小激活因子-SMAF1。与皮下WAT相比，SMAF1在小鼠腹腔WAT组织中富集。此外，SMAF1在肥胖和脂肪生理学中心的激素和细胞因子中显示出不同的调节。SMAF1基因定位到一个包含新的肥胖数量性状位点的染色体区域。SMAF1转录本编码80个氨基酸的全新分子。SMAF1不属于任何已知的蛋白家族，但具有典型的核激素受体LXXLL相互作用基序。初步数据表明，当SMAF1融合到Gal4 DNA结合域时，SMAF1是一个强大的转录激活因子，并且SMAF1可以增强PPAR？介导的转录信号。有人提出SMAF1在脂肪生物学中起关键作用。SMAF1在脂肪细胞信号传导、分化和功能中的作用将在本次R21应用中通过三个具体目标确定：1)异位SMAF1对3T3-L1体外脂肪形成模型的影响2)。SMAF1对PPARgamma转录信号的影响和3)。SMAF1结合伴侣的鉴定。