Hannah-Shmouni Fady, Faucz Fabio R, Stratakis Constantine A
Program on Developmental Endocrinology and Genetics (PDEGEN), Section on Endocrinology and Genetics (SEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) , Bethesda, MD , USA.
Front Endocrinol (Lausanne). 2016 Aug 30;7:111. doi: 10.3389/fendo.2016.00111. eCollection 2016.
Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs.
环磷腺苷（cAMP）依赖性信号通路的改变与大多数导致库欣综合征（CS）的良性肾上腺皮质肿瘤（ACT）有关。磷酸二酯酶（PDE）是调节环核苷酸水平的酶，包括环磷酸腺苷（cAMP）。两种结合cAMP的PDE，即PDE11A和PDE8B中的失活突变及其他功能变异，易引发ACT。这两个基因与ACT的关联最初是在微结节性双侧肾上腺皮质增生患者的全基因组关联研究中发现的。此后，在其他ACT中也发现了PDE11A或PDE8B基因变异，包括大结节性肾上腺皮质增生和分泌皮质醇的腺瘤。此外，在遗传性和散发性睾丸生殖细胞肿瘤以及前列腺癌中也发现了PDE11A表达下调和该基因的失活变异。PDE可能主要通过其对cAMP水平的作用增加ACT形成的风险，但也可能存在其他作用。在本报告中，我们综述了目前已知的关于PDE11A和PDE8B及其与ACT易感性的关系。
