The role of p63 in hair follicle stem cells and cancer

描述（由申请人提供）：p63基因编码皮肤及其附属物正常发育和体内平衡所需的几种转录因子。尽管p63在表皮中的作用已经被证实，但p63在毛囊（HF）中的作用仍然难以捉摸。p63在HF生物学中的作用是基于观察到由p63突变引起的外胚层发育不良患者发生毛干异常。然而，导致这些毛发异常的病理机制尚未阐明。基于我们的初步发现，我们提出p63在HF干细胞中起作用。在特异性目标1中，我们将通过从基因工程小鼠的凸起干细胞中去除p63来验证这一假设。对这些小鼠的分析将确定p63是否在鼓包干细胞存活、更新或激活中起作用。在人类皮肤鳞状细胞癌（SCCs）中也观察到p63的表达减少，SCCs是一种起源于隆起干细胞的肿瘤类型。然而，这一观察结果的功能意义尚不清楚。我们的初步研究结果表明，表皮和毛囊中p63的普遍下调促进了皮肤SCC的发展。在Specific Aim 2中，我们将使用基因工程小鼠进一步确定p63缺失在皮肤SCC肿瘤发生过程中的作用。我们将确定在存在癌基因激活的情况下，从凸起干细胞中切除p63是否会导致皮肤肿瘤易感性增加。此外，我们将确定从已建立的肿瘤中切除p63是否会加速肿瘤进展。总的来说，这些研究将为p63在稳态和病理条件下在鼓包干细胞中的作用提供新的见解。这些研究将对治疗p63相关外胚层发育不良患者的头发异常以及皮肤癌患者的治疗产生影响。

DESCRIPTION (provided by applicant): The p63 gene encodes several transcription factors that are required for normal development and homeostasis of the skin and its appendages. Although the role for p63 in the epidermis has been well-established, the role for p63 in hair follicles (HF) has remained largely elusive. A role for p63 in HF biology has been suggested based on the observation that hair shaft abnormalities develop in patients with ectodermal dysplasias caused by p63 mutations. However, the pathological mechanisms that lead to these hair abnormalities have not been elucidated. Based on our preliminary findings, we propose that p63 functions in HF stem cells of the bulge. In Specific Aim 1, we will test this hypothesis by ablating p63 from bulge stem cells in genetically engineered mice. Analysis of these mice will define whether p63 functions in bulge stem cell survival, renewal, or activation. Reduced p63 expression has also been observed in human skin squamous cell carcinomas (SCCs), a tumor type that originates from bulge stem cells. However, the functional significance of this observation is not known. Our preliminary findings indicate that a general downregulation of p63 in the epidermis and hair follicles facilitates skin SCC development. In Specific Aim 2, we will further define the role of p63 loss during skin SCC tumorigenesis using genetically engineered mice. We will determine whether ablating p63 from bulge stem cells, in the presence of oncogene activation, results in increased skin tumor susceptibility. Further, we will determine whether ablating p63 from established tumors leads to accelerated tumor progression. Collectively, these studies will provide novel insights into the role of p63 in bulge stem cells under homeostatic and pathological conditions. These studies will have implications for the treatment of hair abnormalities in patients with p63-related ectodermal dysplasias as well as for the treatment of patients with skin cancer.