Regulation of Salivary Cell Apoptosis by PKC

产品说明：细胞凋亡是由生理刺激和细胞毒素引发的细胞死亡程序，并且该途径中的缺陷与广泛的疾病相关。凋亡途径的遗传破坏是肿瘤细胞的共同特征，并且可能是许多肿瘤对化疗药物的抗性的基础。在唾液腺中，细胞凋亡障碍有助于唾液腺肿瘤和干燥综合征（一种自身免疫性疾病）的发展。丝氨酸/苏氨酸蛋白激酶的信号转导在各种刺激诱导的细胞凋亡中起着重要作用。本实验室的一个长期目标是了解蛋白激酶C（PKC）如何调节唾液腺泡细胞凋亡。在这个应用程序中，我们将集中在了解这个家庭的成员之一，PKCd，调节细胞凋亡。在之前的研究中，我们已经表明PKCd是多种细胞毒素诱导的细胞凋亡早期事件所必需的。此外，我们已经表明，PKCd易位到细胞核中的细胞凋亡信号的反应，细胞核PKCd是细胞凋亡所需的。虽然这些研究定义了一个必不可少的作用，PKCd在唾液腺泡细胞凋亡，我们知道很少PKCd是如何激活响应凋亡信号，或激活PKCd如何调节凋亡机制。我们证实上游酪氨酸激酶对PKCd的磷酸化调节其促凋亡功能，并且活化的PKCd易位到细胞核，在那里它调节凋亡机制中关键蛋白的丰度或活性。在本申请的目的1中，我们将探索PKCd酪氨酸磷酸化的机制及其在细胞凋亡中的功能意义。在目标2中，我们将询问PKCd是否通过激活下游信号转导途径发挥作用，特别关注信号转导和转录激活因子（STAT）途径。在目标3中，我们将探索凋亡细胞中PKCd的核靶点。在凋亡细胞中调节PKCd活化和下游信号传导的途径的鉴定将使得能够开发旨在促进或抑制该组织中的凋亡的策略。我们的研究结果也将适用于其他上皮细胞模型中的细胞凋亡，并可能对开发针对其他上皮源性肿瘤（如乳腺和胰腺中出现的肿瘤）的治疗方法具有重要意义。

DESCRIPTION: Apoptosis is a program of cell death initiated by physiological stimuli and cellular toxins, and defects in this pathway are associated with a wide range of disorders. Genetic disruption of the apoptotic pathway is a common feature of tumor cells and may underlie the resistance of many tumors to chemotherapeutic drugs. In the salivary gland, disorders of apoptosis contribute to the development of salivary gland tumors and Sj¿gren's syndrome, an autoimmune disorder. Signal transduction by serine/threonine protein kinases plays an essential role in apoptosis induced by a variety of stimuli. A long-term goal of my lab is to understand how protein kinase C (PKC) modulates salivary acinar cell apoptosis. In this application we will focus on understanding how one member of this family, PKCd, regulates apoptosis. In previous studies we have shown that PKCd is required for an early event in apoptosis induced by a wide variety of cell toxins. Furthermore, we have shown that PKCd translocates to the nucleus in response to apoptotic signals, and that nuclear PKCd is required for apoptosis. While these studies define an essential role for PKCd in salivary acinar cell apoptosis, we know little about how PKCd is activated in response to apoptotic signals, or how activated PKCd regulates the apoptotic machinery. We posit that phosphorylation of PKCd by an upstream tyrosine kinase(s) regulates its pro-apoptotic function and that activated PKCd translocates to the nucleus where it regulates the abundance or activity of key proteins in the apoptotic machinery. In Aim 1 of this application we will explore the mechanism of PKCd tyrosine phosphorylation and its functional significance in apoptosis. In Aim 2 we will ask if PKCd functions by activating downstream signal transduction pathways, with a particular focus on the Signal Transducer and Activator of Transcription (STAT) pathway. In Aim 3 we will explore nuclear targets of PKCd in apoptotic cells. The identification of the pathways which regulate PKCd activation and downstream signaling in apoptotic cells will enable the development of strategies Aimed at promoting or inhibiting apoptosis in this tissue. Our results will also be applicable to apoptosis in other epithelial cell models, and may have important implications for the development of therapies directed against other epithelial derived tumors such as those that arise in the breast and pancreas.