Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Curr Mol Med. 2009 Jun;9(5):527-45. doi: 10.2174/156652409788488784.
Apoptosis, a programmed cell death mechanism, is a fundamental process during the normal development and somatic maintenance of all multicellular organisms and thus is highly conserved and tightly regulated through numerous signaling pathways. Apoptosis is of particular clinical importance as its dysregulation contributes significantly to numerous human diseases, primarily through changes in the expression and activation of key apoptotic regulators. Each of the four families of heterotrimeric G proteins (G(s), G(i/o), G(q/11) and G(12/13)) has been implicated in numerous cellular signaling processes, including proliferation, transformation, migration, differentiation, and apoptosis. Heterotrimeric G protein signaling is an important but not widely studied mechanism regulating apoptosis. G protein Signaling and Apoptosis broadly cover two large bodies of literature and share numerous signaling pathways. Examination of the intersection between these two areas is the focus of this review. Several studies have implicated signaling through each of the four heterotrimeric G protein families to regulate apoptosis within numerous disease contexts, but the mechanism(s) are not well defined. Each G protein family has been shown to stimulate and/or inhibit apoptosis in a context-dependent fashion through regulating numerous downstream effectors including the Bcl-2 family, NF-kappaB, PI3 Kinase, MAP Kinases, and small GTPases. These cell-type specific and G protein coupled receptor dependent effects have led to a complex body of literature of G protein regulation of apoptosis. Here, we review the literature and summarize apoptotic signaling through each of the four heterotrimeric G protein families (and the relevant G protein coupled receptors), and discuss limitations and future directions for research on regulating apoptosis through G protein coupled mechanisms. Continued investigation in this field is essential for the identification of important targets for pharmacological intervention in numerous diseases.
细胞凋亡是一种程序性细胞死亡机制，是所有多细胞生物正常发育和体细胞维持的基础过程，因此通过许多信号通路高度保守和严格调控。细胞凋亡在临床上非常重要，因为其失调会导致许多人类疾病，主要是通过关键凋亡调节剂的表达和激活的变化。四种三聚体 G 蛋白家族（G(s)、G(i/o)、G(q/11)和 G(12/13)）都参与了许多细胞信号转导过程，包括增殖、转化、迁移、分化和凋亡。三聚体 G 蛋白信号转导是调节细胞凋亡的重要但尚未广泛研究的机制。G 蛋白信号转导和细胞凋亡广泛涵盖了两大部分文献，并共享许多信号通路。检查这两个领域的交叉点是本综述的重点。有几项研究表明，在许多疾病背景下，通过调节许多下游效应物，包括 Bcl-2 家族、NF-κB、PI3 激酶、MAP 激酶和小 GTP 酶，四种三聚体 G 蛋白家族中的每一种都参与了信号转导以调节细胞凋亡。每种 G 蛋白家族都被证明可以通过调节许多下游效应物（包括 Bcl-2 家族、NF-κB、PI3 激酶、MAP 激酶和小 GTP 酶）以依赖细胞类型和 G 蛋白偶联受体的方式刺激和/或抑制细胞凋亡。这些细胞类型特异性和 G 蛋白偶联受体依赖性效应导致了大量关于 G 蛋白调节细胞凋亡的文献。在这里，我们综述了文献，并总结了通过四种三聚体 G 蛋白家族（和相关的 G 蛋白偶联受体）的细胞凋亡信号转导，并讨论了通过 G 蛋白偶联机制调节细胞凋亡的研究的局限性和未来方向。该领域的持续研究对于确定许多疾病中药物干预的重要靶标至关重要。
