Neuronal apoptosis linked to EgIN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer
Neuronal apoptosis linked to EgIN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer
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DOI：
10.1016/j.ccr.2005.06.015
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发表时间：
2005-08-01
期刊：
影响因子：
50.3
通讯作者：
Schlisio, S
中科院分区：
文献类型：
--
作者：
Lee, S;Nakamura, E;Schlisio, S
种系NF1、c - RET、SDH和VHL突变导致家族性嗜铬细胞瘤。嗜铬细胞瘤来源于交感神经神经元前体细胞。在正常发育过程中，随着神经生长因子（NGF）变得有限，许多这些细胞会经历依赖c - Jun的凋亡。NF1编码神经生长因子受体TrkA的一种GAP蛋白，NF1突变会促进在神经生长因子缺失后的细胞存活。我们发现与嗜铬细胞瘤相关的c - RET和VHL突变导致JunB增加，这减弱了神经生长因子缺失后神经元的凋亡。我们还发现脯氨酰羟化酶EgIN3在c - Jun下游发挥作用，并且在这种情况下，在三个EgIN家族成员中是细胞凋亡所特需的。此外，EgIN3的促凋亡活性需要SDH活性，因为EgIN3受到琥珀酸的反馈抑制。这些研究表明，发育性凋亡失败在嗜铬细胞瘤的发病机制中起作用。
Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EgIN3 acts downstream of c-Jun and is specifically required among the three EgIN family members for apoptosis in this setting. Moreover, EgIN3 proapoptotic activity requires SDH activity because EgIN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.