Regulatory subunits of PKA define an axis of cellular proliferation/differentiation in ovarian cancer cells
Regulatory subunits of PKA define an axis of cellular proliferation/differentiation in ovarian cancer cells
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DOI：
10.1186/1755-8794-1-43
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发表时间：
2008-09-26
影响因子：
2.7
通讯作者：
Cho-Chung, Yoon S.
中科院分区：
文献类型：
--
作者：
Cheadle, Chris;Nesterova, Maria;Cho-Chung, Yoon S.
背景资料：cAMP依赖性蛋白激酶（PKA）的调节亚基以两种亚型RI和RII存在，其区分PKA同工酶I型（PKA-I）和II型（PKA-II）。从各种不同的实验方法中获得的证据表明，细胞中I型和II型PKA的相对水平可以在确定细胞生长和分化之间的平衡中发挥主要作用。为了在整体水平上表征PKA I型和II型调节亚基对基因转录的影响，将RI α和RII β的PKA调节亚基基因稳定转染到卵巢癌细胞系（OVCAR 8）中。微阵列分析显示RI α、RII β和亲代OVCAR细胞之间的基因表达发生了同样深刻的变化。RI α细胞中特异性上调的基因高度富集了参与细胞生长的途径，而RII β细胞中上调的基因富集了参与分化的途径。一大组基因（类似于3600个）在RI α、亲本和RII β细胞之间沿着增殖/分化轴被沿着调节。RI α/wt和RII β/wt基因调控显示由两个独立的和不同的基因集分析方法是强烈的交叉相关的一个通用模型的cellulardifferentiation.Conclusion：PKA调节亚基在卵巢癌细胞系中的过表达显着影响细胞表型。增殖表型与最近发现的预测卵巢癌预后不良的临床生物标志物密切相关，这表明PKA调节在疾病进展中可能起关键作用。
Background: The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in two isoforms, RI and RII, which distinguish the PKA isozymes, type I (PKA-I) and type II (PKA-II). Evidence obtained from a variety of different experimental approaches has shown that the relative levels of type I and type II PKA in cells can play a major role in determining the balance between cell growth and differentiation. In order to characterize the effect of PKA type I and type II regulatory subunits on gene transcription at a global level, the PKA regulatory subunit genes for RI alpha and RII beta were stably transfected into cells of the ovarian cancer cell line (OVCAR8).Results: RI alpha transfected cells exhibit hyper-proliferative growth and RII beta transfected cells revert to a relatively quiescent state. Profiling by microarray revealed equally profound changes in gene expression between RI alpha, RII beta, and parental OVCAR cells. Genes specifically up-regulated in RI alpha cells were highly enriched for pathways involved in cell growth while genes up-regulated in RII beta cells were enriched for pathways involved in differentiation. A large group of genes (similar to 3600) was regulated along an axis of proliferation/differentiation between RI alpha, parental, and RII beta cells. RI alpha/wt and RII beta/wt gene regulation was shown by two separate and distinct gene set analytical methods to be strongly cross-correlated with a generic model of cellular differentiation.Conclusion: Overexpression of PKA regulatory subunits in an ovarian cancer cell line dramatically influences the cell phenotype. The proliferation phenotype is strongly correlated with recently identified clinical biomarkers predictive of poor prognosis in ovarian cancer suggesting a possible pivotal role for PKA regulation in disease progression.