Salivary Acinar Cell Apoptosis: Regulation of p53 by Akt

唾液腺泡细胞凋亡：Akt 对 p53 的调节

• 批准号: 7060433
• 负责人: KIRSTEN H LIMESAND
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060433
• 关键词: DNA damage; acinar cell; apoptosis; enzyme activity; enzyme mechanism; gamma radiation; gene induction /repression; genetic transcription; genetically modified animals; laboratory mouse; p53 gene /protein; salivary glands; serine threonine protein kinase; tissue /cell culture

DESCRIPTION (provided by applicant): Apoptosis plays a crucial role in mammalian development and complex control mechanisms exist to regulate these signaling pathways. Aberrant apoptosis of the salivary glands is induced by secondary side effects of head and neck irradiation, chemotherapeutics, or Sjogren's syndrome. p53 is an important regulator of apoptosis induced by DNA damage. The identification of two p53 homologues, p73 and p63, along with the selective activation of apoptotic target genes by these different homologues have added additional complexity in the understanding of how the decision to undergo apoptosis is executed. Increased expression of the p53 responsive genes bax and Fas has been shown in the lacrimal and salivary glands of Sjogren's syndrome patients and p53 is hypothesized to be associated in the pathogenesis of autoimmune disorders. The general goal of this proposal is to understand the induction of the p53 responsive genes in salivary acinar cells and regulation of this activity by the pro-survival serine/threonine protein kinase Akt. Specifically, the role Akt serves in suppressing apoptosis following DNA damage and the interaction with the p53 family of proteins will be examined. We hypothesize that Akt suppresses DNA damage induced apoptosis through a modulation of the p53 family of transcription factors. Specific Aim 1 will define the in vivo mechanisms by which Akt suppresses gamma-irradiation-induced apoptosis in the salivary gland. Specific Aim 2 will identify the requirement for p53 transcriptional activation in gamma-irradiation-induced salivary gland apoptosis. Specific Aim 3 will examine the induction of p73 activity in salivary acinar cells and the effect of its suppression by activated Akt. Specific Aim 4 will investigate the functions of p63 in salivary acinar cells and the ability of Akt to regulate these functions. Transiently cultured primary submandibular or parotid acinar cells isolated from mice provide a unique environment to examine the regulation of apoptosis. In addition, a transgenic mouse strain that expresses activated Akt has been used as a novel reagent in understanding the suppression of apoptosis induced by a variety of stimuli in salivary acinar cells. New understanding of the fundamental biological process of p53 regulation could have a powerful impact on clinical therapeutics for salivary glands.

描述（由申请人提供）：细胞凋亡在哺乳动物发育中起着至关重要的作用，存在复杂的控制机制来调节这些信号通路。唾液腺的异常凋亡是由头颈部放射、化疗或干燥综合征的继发副作用引起的。p53是DNA损伤诱导细胞凋亡的重要调节因子。两种p53同源物p73和p63的鉴定，沿着这些不同同源物对凋亡靶基因的选择性激活，增加了理解如何执行进行凋亡的决定的额外复杂性。在干燥综合征患者的泪腺和唾液腺中已经显示p53应答基因bax和Fas的表达增加，并且假设p53与自身免疫性疾病的发病机制相关。 这个建议的总体目标是了解诱导的p53应答基因在唾液腺泡细胞和调节这种活性的促生存丝氨酸/苏氨酸蛋白激酶Akt。具体而言，Akt在抑制DNA损伤后细胞凋亡中的作用以及与p53蛋白家族的相互作用将被检查。我们推测Akt通过调节p53家族转录因子抑制DNA损伤诱导的细胞凋亡。具体目标1将定义Akt抑制唾液腺中γ辐射诱导的细胞凋亡的体内机制。具体目标2将确定在γ射线诱导的唾液腺细胞凋亡中p53转录激活的要求。具体目标3将检查唾液腺泡细胞中p73活性的诱导以及激活的Akt对其抑制的效果。具体目标4将研究p63在唾液腺泡细胞中的功能以及Akt调节这些功能的能力。瞬时培养的原代下颌下或腮腺腺泡细胞从小鼠中分离提供了一个独特的环境，检查细胞凋亡的调节。此外，表达活化Akt的转基因小鼠品系已被用作了解唾液腺泡细胞中由各种刺激诱导的细胞凋亡抑制的新试剂。对p53调控的基本生物学过程的新理解可能对唾液腺的临床治疗产生强大的影响。