14-3-3 Mediated regulation of the tumor suppressor protein, RASSF1A
14-3-3 Mediated regulation of the tumor suppressor protein, RASSF1A
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DOI：
10.1007/s10495-009-0451-6
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发表时间：
2010-02-01
期刊：
影响因子：
7.2
通讯作者：
Baksh，Shairaz
中科院分区：
文献类型：
--
作者：
Abu Ghazaleh，Haya;Chow，Renfred S.;Baksh，Shairaz
死亡受体依赖性细胞凋亡是细胞生长调控的重要机制。研究表明，Ras关联结构域家族蛋白1A （RASSF1A）是一种参与死亡受体依赖性细胞凋亡的肿瘤抑制蛋白。然而，目前尚不清楚rassf1a介导的细胞死亡是如何启动的。我们现在已经详细了解了14-3-3依赖于rassf1a介导的细胞死亡的调控。我们证明RASSF1A与14-3-3的基础关联在肿瘤坏死因子α (TNFα)或TNFα相关的凋亡诱导配体（TRAIL）刺激后丧失。在14-3-3关联缺失后，RASSF1A与凋亡调节剂（MOAP-1）相关，随后死亡受体与TNFα受体1 （TNF-R1）或TRAIL受体1 （TRAIL- r1）相关。14-3-3关联需要丝氨酸/苏氨酸激酶、糖原合成酶激酶3β (GSK-3β)在丝氨酸175、178和179上的基础磷酸化。这些关键丝氨酸的突变导致14-3-3关联缺失，RASSF1A更早募集到MOAP-1、TNF-R1和TRAIL-R1。此外，与含有野生型RASSF1A的稳定细胞相比，含有RASSF1A三丝氨酸突变体[丝氨酸(S) 175到丙氨酸(a) [S175A]、S178A和S179A]的稳定细胞在TNFα刺激后增加了基底细胞死亡、增强了Annexin V染色和增强了聚adp核糖聚合酶（PARP）的裂解。因此，rassf1a介导的细胞死亡受到14-3-3关联的严格控制。
Death receptor-dependent apoptosis is an important mechanism of growth control. It has been demonstrated that Ras association domain family protein 1A (RASSF1A) is a tumor suppressor protein involved in death receptor-dependent apoptosis. However, it is unclear how RASSF1A-mediated cell death is initiated. We have now detailed 14-3-3 dependent regulation of RASSF1A-mediated cell death. We demonstrate that basal association of RASSF1A with 14-3-3 was lost following stimulation with tumor necrosis factor alpha (TNFα) or TNFα related apoptosis inducing ligand (TRAIL). Subsequent to the loss of 14-3-3 association, RASSF1A associated with modulator of apoptosis (MOAP-1) followed by death receptor association with either TNFα receptor 1 (TNF-R1) or TRAIL receptor 1 (TRAIL-R1). 14-3-3 association required basal phosphorylation by the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β), on serine 175, 178, and 179. Mutation of these critical serines resulted in the loss of 14-3-3 association and earlier recruitment of RASSF1A to MOAP-1, TNF-R1, and TRAIL-R1. Furthermore, stable cells containing a triple serine mutant of RASSF1A [serine (S) 175 to alanine (A) [S175A], S178A, and S179A] resulted in increased basal cell death, enhanced Annexin V staining and enhanced cleavage of poly (ADP-ribose) polymerase (PARP) following TNFα stimulation when compared to stable cells containing wild type RASSF1A. RASSF1A-mediated cell death is, therefore, tightly controlled by 14-3-3 association.