Robinson-White Audrey J, Leitner Wolfgang W, Aleem Eiman, Kaldis Philipp, Bossis Ioannis, Stratakis Constantine A
Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892, USA.
Cancer Res. 2006 Nov 1;66(21):10603-12. doi: 10.1158/0008-5472.CAN-06-2200.
The multiple neoplasia syndrome Carney complex (CNC) is caused by heterozygote mutations in the gene, which codes for the RIalpha regulatory subunit (PRKAR1A) of protein kinase A. Inactivation of PRKAR1A and the additional loss of the normal allele lead to tumors in CNC patients and increased cyclic AMP signaling in their cells, but the oncogenetic mechanisms in affected tissues remain unknown. Previous studies suggested that PRKAR1A down-regulation may lead to increased mitogen-activated protein kinase (MAPK) signaling. Here, we show that, in lymphocytes with PRKAR1A-inactivating mutations, there is increased extracellular signal-regulated kinase (ERK) 1/2 and B-raf phosphorylation and MAPK/ERK kinase 1/2 and c-Myc activation, whereas c-Raf-1 is inhibited. These changes are accompanied by increased cell cycle rates and decreased apoptosis that result in an overall net gain in proliferation and survival. In conclusion, inactivation of PRKAR1A leads to widespread changes in molecular pathways that control cell cycle and apoptosis. This is the first study to show that human cells with partially inactivated RIalpha levels have increased proliferation and survival, suggesting that loss of the normal allele in these cells is not necessary for these changes to occur.
多发性肿瘤综合征卡尼复合征（CNC）由该基因的杂合突变引起，该基因编码蛋白激酶A的RIα调节亚基（PRKAR1A）。PRKAR1A的失活以及正常等位基因的额外缺失导致CNC患者发生肿瘤，并使其细胞中的环磷酸腺苷信号增加，但受影响组织中的致癌机制仍不清楚。先前的研究表明，PRKAR1A的下调可能导致丝裂原活化蛋白激酶（MAPK）信号增加。在此，我们表明，在具有PRKAR1A失活突变的淋巴细胞中，细胞外信号调节激酶（ERK）1/2和B-raf的磷酸化增加，MAPK/ERK激酶1/2和c-Myc被激活，而c-Raf-1受到抑制。这些变化伴随着细胞周期速率的增加和凋亡的减少，从而导致增殖和存活的总体净增加。总之，PRKAR1A的失活导致控制细胞周期和凋亡的分子途径发生广泛变化。这是第一项表明RIα水平部分失活的人类细胞增殖和存活增加的研究，表明这些细胞中正常等位基因的缺失对于这些变化的发生不是必需的。
