Heyerdahl S L, Boikos S, Horvath A, Giatzakis C, Bossis I, Stratakis C A
Section on Endocrinology & Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Horm Metab Res. 2008 Jun;40(6):391-7. doi: 10.1055/s-2008-1058089. Epub 2008 Mar 6.
Bloom syndrome is a genetic disorder associated with chromosomal instability and a predisposition to tumors that is caused by germline mutations of the BLM gene, a RecQ helicase. Benign adrenocortical tumors display a degree of chromosomal instability that is more significant than benign tumors of other tissues. Cortisol-producing hyperplasias, such as primary pigmented nodular adrenocortical disease (PPNAD), which has been associated with protein kinase A (PKA) abnormalities and/or PRKAR1A mutations, also show genomic instability. Another RecQ helicase, WRN, directly interacts with the PRKAR1B subunit of PKA. In this study, we have investigated the PRKAR1A expression in primary human Bloom syndrome cell lines with known BLM mutations and examined the BLM gene expression in PPNAD and other adrenal tumor tissues. PRKAR1A and other protein kinase A (PKA) subunits were expressed in Bloom syndrome cells and their level of expression differed by subunit and cell type. Overall, fibroblasts exhibited a significant decrease in protein expression of all PKA subunits except for PRKAR1A, a pattern that has been associated with neoplastic transformation in several cell types. The BLM protein was upregulated in PPNAD and other hyperplasias, compared to samples from normal adrenals and normal cortex, as well as samples from cortisol- and aldosterone-producing adenomas (in which BLM was largely absent). These data reveal an inverse relationship between BLM and PRKAR1A: BLM deficiency is associated with a relative excess of PRKAR1A in fibroblasts compared to other PKA subunits; and PRKAR1A deficiency is associated with increased BLM protein in adrenal hyperplasias.
布卢姆综合征是一种与染色体不稳定和肿瘤易感性相关的遗传性疾病，由RecQ解旋酶BLM基因的种系突变引起。良性肾上腺皮质肿瘤表现出一定程度的染色体不稳定，其程度比其他组织的良性肿瘤更为显著。产生皮质醇的增生性疾病，如与蛋白激酶A（PKA）异常和/或PRKAR1A突变相关的原发性色素性结节性肾上腺皮质病（PPNAD），也表现出基因组不稳定。另一种RecQ解旋酶WRN直接与PKA的PRKAR1B亚基相互作用。在本研究中，我们调查了已知BLM突变的原发性人类布卢姆综合征细胞系中PRKAR1A的表达，并检测了PPNAD和其他肾上腺肿瘤组织中BLM基因的表达。PRKAR1A和其他蛋白激酶A（PKA）亚基在布卢姆综合征细胞中表达，其表达水平因亚基和细胞类型而异。总体而言，成纤维细胞中除PRKAR1A外的所有PKA亚基的蛋白表达均显著降低，这种模式在几种细胞类型中与肿瘤转化有关。与正常肾上腺和正常皮质的样本以及产生皮质醇和醛固酮的腺瘤样本（其中BLM基本缺失）相比，PPNAD和其他增生性疾病中BLM蛋白上调。这些数据揭示了BLM与PRKAR1A之间的负相关关系：与其他PKA亚基相比，成纤维细胞中BLM缺乏与PRKAR1A相对过量有关；而PRKAR1A缺乏与肾上腺增生中BLM蛋白增加有关。
