Sufu-interacting proteins provide novel insight into mammalian Hedgehog signaling

 描述(申请人提供)：这项研究旨在填补我们对哺乳动物Hedgehog(HH)信号机制理解的一个主要空白。HH信号的中断会导致先天性异常和癌症的发展。阻断HH信号的药物已经用于治疗与HH信号异常有关的人类癌症的临床试验。我们在这一应用中的研究重点是融合抑制因子(Sufu)，它是HH信号的主要负调控因子。通过以Sufu为工具的蛋白质组学方法，我们已经确定了HH信号的新成员，包括p66？和MycBP。我们的初步研究采用了功能增益和功能丧失的方法，提供了强有力的证据来支持这样一个模型，在该模型中，p66ç在调节HH信号中起着负面作用，而MycBP起着积极作用。我们还通过对Sufu突变表型的分析，揭示了差异HH反应的新的复杂性水平。这些发现为理解HH信号是如何传导的提供了一个新的概念框架。基于这些新的发现，我们将解决HH信号在这一应用中的一个中心问题：如何通过调节Sufu和Gli功能来产生分级的HH反应。我们的具体目标是(1)验证p66？抑制和MycBP增强Sufu在HH信号中的核功能的假说；(2)研究p66？和MycBP在HH信号中调节Sufu功能的分子机制；以及(3)研究Sufu和HH反应对Gli蛋白的差异调控。综上所述，这些研究将为哺乳动物HH信号提供新的见解，并为HH相关疾病的诊断和治疗奠定基础。

 DESCRIPTION (provided by applicant): This study aims to fill a major gap in our mechanistic understanding of mammalian Hedgehog (Hh) signaling. Disrupted Hh signaling leads to congenital anomalies and cancer development. Drugs that block Hh signaling have been used in clinical trials for treating human cancers related to aberrant Hh signaling. Our research in thi application focuses on Suppressor of fused (Sufu), a major negative regulator of Hh signaling. Through a proteomic approach using Sufu as a tool, we have identified new players of Hh signaling, including p66ß and Mycbp. Our preliminary studies employing both gain- and loss-of function approaches provide strong evidence to support a model in which p66ß plays a negative role while Mycbp plays a positive role in regulating Hh signaling. We also uncovered a new level of complexity in differential Hh responses through analysis of Sufu mutant phenotypes. These findings offer a novel conceptual framework for understanding how the Hh signal is transduced. Based on these novel discoveries, we will address a central question of Hh signaling in this application: how graded Hh responses are produced through regulation of Sufu and Gli function. Our specific aims are (1) To test the hypothesis that p66ß inhibits and Mycbp potentiates Sufu's nuclear function in Hh signaling; (2) To investigate the molecular mechanisms by which p66ß and Mycbp regulate Sufu function in Hh signaling; and (3) To study differential regulation of Gli proteins by Sufu and Hh responses. Taken together, these studies will offer new insight into mammalian Hh signaling and establish the foundation for diagnosis and treatment of Hh-related diseases.