Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Science. 2014 May 23;344(6186):917-20. doi: 10.1126/science.1252328.
Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.
库欣综合征是由肾上腺皮质腺产生过多的皮质醇引起的。在促肾上腺皮质激素非依赖性库欣综合征中，皮质醇的过量产生主要归因于肾上腺皮质腺瘤，其潜在的分子发病机制尚不清楚。我们报告了 PRKACA 中的热点突变（L206R），该突变为环腺苷酸（cAMP）依赖性蛋白激酶（PKA）的催化亚基编码，在超过 50%的与促肾上腺皮质激素非依赖性库欣综合征相关的肾上腺皮质腺瘤病例中发现。L206R PRKACA 突变体消除了其与 PKA 的调节亚基（PRKAR1A）的结合，PRKAR1A 抑制 PRKACA 的催化活性，导致组成型、cAMP 非依赖性 PKA 激活。这些结果强调了促肾上腺皮质激素非依赖性库欣综合征中体细胞突变对 cAMP/ PKA 信号的非依赖性激活的主要作用，为该综合征的诊断和治疗提供了新的思路。
