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: 7110456
• 负责人: KIRSTEN H LIMESAND
• 金额: $ 7.06万
• 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/7110456
• 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，并且存在复杂的控制机制来调节这些信号传导途径。头颈部放疗、化疗或干燥综合征的继发副作用会诱导唾液腺异常凋亡。 p53 是 DNA 损伤诱导的细胞凋亡的重要调节因子。两个 p53 同源物 p73 和 p63 的鉴定，以及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细胞凋亡决定的复杂性。干燥综合征患者的泪腺和唾液腺中 p53 反应基因 bax 和 Fas 的表达增加，并且推测 p53 与自身免疫性疾病的发病机制有关。 该提案的总体目标是了解唾液腺泡细胞中 p53 反应基因的诱导以及促存活丝氨酸/苏氨酸蛋白激酶 Akt 对该活性的调节。具体来说，将检查 Akt 在 DNA 损伤后抑制细胞凋亡中的作用以及与 p53 蛋白家族的相互作用。我们假设 Akt 通过调节 p53 转录因子家族来抑制 DNA 损伤诱导的细胞凋亡。具体目标 1 将定义 Akt 抑制 γ 辐射诱导的唾液腺细胞凋亡的体内机制。具体目标 2 将确定伽马射线照射诱导的唾液腺细胞凋亡中 p53 转录激活的需要。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。从小鼠中分离出的瞬时培养的原代颌下或腮腺腺泡细胞为检查细胞凋亡的调节提供了独特的环境。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各种刺激诱导的细胞凋亡抑制的新型试剂。对 p53 调节基本生物学过程的新认识可能会对唾液腺的临床治疗产生巨大影响。