Regulating Gli Function in Hair Follicle Progenitors

调节毛囊祖细胞中的 Gli 功能

• 批准号: 8999344
• 负责人: Anthony E Oro
• 金额: $ 4.98万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999344
• 关键词: Affect; Basal cell carcinoma; Binding; Biological Assay; Cilia; Collaborations; Complex; DNA; DNA Binding; DNA Binding Domain; Diagnosis; Erinaceidae; Evolution; Funding; Gene Activation; Growth; Hair follicle structure; Health; Human; In Vitro; Location; Mediating; Modeling; Modification; Neoplasm Metastasis; Nucleic Acid Regulatory Sequences; Oncogenic; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Proteomics; RNA Sequences; Regulation; Relative (related person); Resistance; Sampling; Skin; Structure; Surface; Testing; Variant; Work; Zinc Fingers; carcinogenesis; enhancing factor; exome sequencing; experience; human SMO protein; in vivo; inhibitor/antagonist; insight; kinetosome; mutant; novel; overexpression; progenitor; receptor; response; smoothened signaling pathway; targeted treatment; transcription factor; transcriptome sequencing; tumor; tumor growth

DESCRIPTION (provided by applicant): Hedgehog (Hh) signaling has emerged as a key growth pathway in human carcinogenesis and inappropriate Hh target gene activation drives the growth of tumors such as skin basal cell carcinomas (BCCs). Experimental support from 5ARO54780 facilitated approval by the FDA of the first therapy aimed at the Smoothened (Smo) receptor. While naïve tumors responded, resistance appears to be common, reiterating the need for developing new therapies targeting the Gli transcription factors downstream of Smo. 5ARO54780 in the prior funding period focused on factors that regulate Gli activity and showed the importance of the primary cilium and the basal body-associated Missing-in- Metastasis. Moreover, a proteomics screen to identify druggable components isolated the oncogenic polarity kinase aPKC-ι/λ and demonstrated that aPKC-ι/λ plays a key role in hedgehog signaling, BCC tumor growth, and Smo inhibitor resistance. In tumors, aPKC-ι/λ phosphorylates and activates Gli1 within the regulatory region of the DNA binding domain at residue Gli T304. By contrast, phosphorylation within the linker region of the DNA binding domain appears to inhibit function, revealing a gap in our understanding how DNA binding domain modifications affect activity. Studies in the next funding period will test the hypothesis that aPKC-ι/λ-mediated DNA binding domain phosphorylation regulates Gli activity and Smo inhibitor resistance by: Determining the consequences of Gli DNA binding domain phosphorylation; Determining how aPKC phosphorylation affects the Gli- DNA interaction; and by 3) Determining the functional consequences of resistant human BCC tumor variants on BCC growth. Completion of the above aims will provide needed information about the pivotal Gli transcription factor and provide insights to help diagnose and treat naïve and resistant hedgehog-dependent tumors.

描述（由申请人提供）：Hedgehog (Hh) 信号传导已成为人类致癌的关键生长途径，不适当的 Hh 靶基因激活会驱动皮肤基底细胞癌 (BCC) 等肿瘤的生长。5ARO54780 的实验支持促进了批准。 FDA 批准了第一种针对 Smoothened (Smo) 受体的疗法，虽然幼稚肿瘤有反应，但耐药性似乎很常见，这再次表明需要开发针对该受体的新疗法。先前资助期间的 Smo.5ARO54780 下游的 Gli 转录因子重点关注调节 Gli 活性的因子，并显示了初级纤毛和基底体相关转移缺失的重要性。此外，还进行了蛋白质组学筛选，以鉴定可药物成分。分离致癌极性激酶 aPKC-ι/λ 并证明 aPKC-ι/λ 在 Hedgehog 信号传导、BCC 肿瘤生长和 Smo 抑制剂中发挥关键作用在肿瘤中，aPKC-ι/λ 在残基 Gli T304 处的 DNA 结合结构域内磷酸化并激活 Gli1，相比之下，DNA 结合结构域的接头区域内的磷酸化似乎会抑制功能，揭示了 Gli1 的功能缺口。我们了解 DNA 结合域修饰如何影响活性，下一个资助期的研究将通过以下方式检验 aPKC-ι/λ 介导的 DNA 结合域磷酸化调节 Gli 活性和 Smo 抑制剂耐药性的假设：确定 Gli DNA 结合域磷酸化的后果；确定 aPKC 磷酸化如何影响 Gli-DNA 相互作用；以及 3) 确定耐药人类 BCC 肿瘤变异对 BCC 生长的功能影响。关键的 Gli 转录因子，并为帮助诊断和治疗幼稚和耐药的刺猬依赖性肿瘤提供见解。