p63 and p73 Signaling in Cell Growth and Cancer

细胞生长和癌症中的 p63 和 p73 信号转导

• 批准号: 8657362
• 负责人: JENNIFER A PIETENPOL
• 金额: $ 2.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657362
• 关键词: Adult; Biological; Biological Models; Breast; Cancer Cell Growth; Cancer Patient; Carcinoma; Cell Survival; Cell model; Cell physiology; Cells; Complex; Data; Data Set; Development; Developmental Process; Epidermis; Epithelial; Epithelial Cells; Family; Family member; Functional disorder; Funding; Gene Expression; Gene Targeting; Generations; Genetic Transcription; Genotoxic Stress; Goals; Human; Knock-out; Knockout Mice; Laboratories; Lead; Malignant Neoplasms; Mammary gland; Mesenchymal; Metabolic; Metabolic stress; Metabolism; Mus; Normal Cell; Organ; Pathway interactions; Play; Predisposition; Process; Prostate; Protein Family; Proteins; Proteomics; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Skin; Stimulus; Stratum Basale; Stress; Structure; Testing; Therapeutic; Time; Tissues; Translating; Tumor Suppression; Tumor Suppressor Proteins; base; cancer therapy; chromatin immunoprecipitation; design; expectation; genetically modified cells; in vivo Model; insight; mouse model; novel; overexpression; protein complex; protein p73; response; stoichiometry; tumor; tumorigenesis; ubiquitin-protein ligase

Although the pivotal role of p53 in tumor suppression remains unchallenged, the role of its family members, p63 and p73 in normal cell function and tumorigenesis is far from certain. Structural similarities and functions of the p53 family of proteins connect them in similar signaling pathways, in both collaborative and antagonistic interactions; however, in vivo models suggest a role for both p63 and p73 in p53-independent developmental and differentiation processes. In particular, p63-null mice lack an epidermis and related structures such as mammary and prostate glands. Interestingly, p63 is expressed in the basal layer of several epithelial tissues such as skin, breast and prostate, and is overexpressed in many squamous and basal-like carcinomas. Evidence suggests that p63 may function in tumors in part through interaction with p73, which is also overexpressed in many human tumors. The goal of the proposed studies is to determine the roles of p63 and p73 in cell metabolism and survival as well as epithelial-mesenchymal crosstalk and transition, and to discover how these roles are deregulated during tumorigenesis. Through generation and integration of comprehensive chromatin immunoprecipitation and microarray data sets, we identified numerous novel p63 and p73 target genes. Based on our findings, we propose the following interrelated hypotheses: (i) p63 and p73 regulate the transcription of unique or shared target genes involved in cell metabolism and survival as well as epithelial-mesenchymal cross-talk and transition; and, (ii) loss of proper p63 and p73 activity will lead to altered cell survival and function resulting in developmental abnormalities or tumorigenesis, depending on the biological time point of dysfunction. These hypotheses will be tested through the following Specific Aims: (1) To analyze select novel target genes uniquely or coordinately regulated by p63 and p73. We will determine the role of these target genes in biologically relevant endpoints downstream of p63 and p73 signaling using organotypic model systems; (2) To analyze p63 and p73 protein complexes and a newly identified protein that interacts with these family members; and (3) To analyze mice with conditional, tissue-specific knock-out of p73. The mice will be characterized in terms of organ and metabolic function and response to stress. The effect of tissue-specific knockout of p63, p73, and p53, alone or in combination, in the mammary gland will be studied to determine the separate or coordinate roles of the family members in adult tissue function, and susceptibility to tumorigenesis. The importance of understanding p63 and p73 regulation and function is underscored by the deregulation of the p53 family in human tumors and the expectation that a mechanistic understanding of the p63 and p73 signaling axes in cancer will translate to therapeutic benefit for cancer patients.

尽管p53在肿瘤抑制中的关键作用仍然没有受到挑战，但其家族成员p63和p73在正常细胞功能和肿瘤发生中的作用还远未确定。 p53 蛋白家族的结构相似性和功能将它们通过相似的信号传导途径（无论是协作还是拮抗相互作用）连接起来；然而，体内模型表明 p63 和 p73 在独立于 p53 的发育和分化过程中发挥作用。特别是，p63缺失小鼠缺乏表皮和相关结构，例如乳腺和前列腺。有趣的是，p63在皮肤、乳腺和前列腺等多种上皮组织的基底层中表达，并且在许多鳞状细胞癌和基底样癌中过度表达。有证据表明，p63 可能部分通过与 p73 相互作用而在肿瘤中发挥作用，而 p73 在许多人类肿瘤中也过度表达。拟议研究的目标是确定 p63 和 p73 在细胞代谢和存活以及上皮-间质串扰和转变中的作用，并发现这些作用在肿瘤发生过程中如何失调。通过生成和整合全面的染色质免疫沉淀和微阵列数据集，我们鉴定了许多新的 p63 和 p73 靶基因。基于我们的发现，我们提出以下相互关联的假设：（i）p63和p73调节参与细胞代谢和存活以及上皮间质串扰和转变的独特或共享靶基因的转录； (ii) 适当的 p63 和 p73 活性的丧失将导致细胞存活和功能改变，从而导致发育异常或肿瘤发生，具体取决于功能障碍的生物学时间点。这些假设将通过以下具体目标进行检验：（1）分析由p63和p73独特或协调调节的选定新靶基因。我们将使用器官模型系统确定这些靶基因在 p63 和 p73 信号下游生物学相关终点中的作用； (2) 分析 p63 和 p73 蛋白复合物以及新鉴定的与这些家族成员相互作用的蛋白； (3) 分析条件性、组织特异性 p73 敲除的小鼠。这些小鼠的特征是器官和代谢功能以及对压力的反应。将研究p63、p73和p53单独或组合的组织特异性敲除在乳腺中的作用，以确定家族成员在成体组织功能和肿瘤发生易感性中的单独或协调作用。人类肿瘤中 p53 家族的失调以及对癌症中 p63 和 p73 信号轴的机制理解将转化为癌症患者的治疗益处的预期，强调了了解 p63 和 p73 调控和功能的重要性。