Development of pheochromocytoma in ceramide synthase 2 null mice.
Development of pheochromocytoma in ceramide synthase 2 null mice.
复制标题
DOI：
10.1530/erc-15-0058
复制
发表时间：
2015-08
影响因子：
3.9
通讯作者：
Futerman AH
中科院分区：
文献类型：
--
作者：
Park WJ;Brenner O;Kogot-Levin A;Saada A;Merrill AH Jr;Pewzner-Jung Y;Futerman AH
嗜铬细胞瘤（PCC）和副神经节瘤是肾上腺髓质、交感神经和副交感神经副神经节的罕见神经内分泌肿瘤，已发现约15个疾病相关基因突变。我们现在记录了一个额外的基因在小鼠中的作用，神经酰胺合成酶2（CerS 2）基因。CerS 2是六种哺乳动物CerS之一，合成具有非常长（C22-C24）酰基链的神经酰胺。CerS 2敲除小鼠已被充分表征，并在包括肝脏、肺和脑在内的几个器官中显示病变。我们现在证明，肾上腺鞘脂酰基链的变化导致肾上腺髓质肿瘤的产生。组织学分析显示，约一半的CerS 2敲除小鼠在约13个月时发生PCC，其余小鼠显示出髓质增生的迹象。尿中的去甲肾上腺素和去甲肾上腺素水平在7个月龄时升高，这与在以后年龄发现的形态异常一致。早在2月龄时就观察到X区中蜡样物质的积累，因此，到6月龄时，老年小鼠显示溶酶体组织蛋白酶水平升高，蛋白酶体活性降低，线粒体复合物IV活性降低。总之，这些发现暗示了一个额外的途径，可以导致PCC的形成，这涉及鞘脂酰基链长度的改变。分析鞘脂在PCC中的作用可能会导致进一步了解PCC发展的机制，并可能暗示鞘脂途径作为这种罕见肿瘤的可能新的治疗靶点。
Pheochromocytoma (PCC) and paraganglioma are rare neuroendocrine tumors of the adrenal medulla and sympathetic and parasympathetic paraganglia, for which mutations in ~15 disease-associated genes have been identified. We now document the role of an additional gene in mice, the ceramide synthase 2 (CerS2) gene. CerS2, one of six mammalian CerS, synthesizes ceramides with very-long (C22–C24) acyl chains. The CerS2 null mouse has been well characterized and displays lesions in several organs including the liver, lung and the brain. We now demonstrate that changes in the sphingolipid acyl chain profile of the adrenal gland lead to the generation of adrenal medullar tumors. Histological analyses revealed that about half of the CerS2 null mice developed PCC by ~13 months, and the rest showed signs of medullary hyperplasia. Norepinephrine and normetanephrine levels in the urine were elevated at 7 months of age consistent with the morphological abnormalities found at later ages. Accumulation of ceroid in the X-zone was observed as early as 2 months of age and as a consequence, older mice displayed elevated levels of lysosomal cathepsins, reduced proteasome activity and reduced activity of mitochondrial complex IV by six months of age. Together, these findings implicate an additional pathway that can lead to PCC formation, which involves alterations in the sphingolipid acyl chain length. Analysis of the role of sphingolipids in PCC may lead to further understanding of the mechanism by which PCC develops, and might implicate the sphingolipid pathway as a possible novel therapeutic target for this rare tumor.