Interaction of the regulatory subunit of the cAMP-dependent protein kinase with PATZ1 (ZNF278).
Interaction of the regulatory subunit of the cAMP-dependent protein kinase with PATZ1 (ZNF278).
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cAMP 依赖性蛋白激酶的调节亚基与 PATZ1 (ZNF278) 的相互作用。
DOI：
10.1016/j.bbrc.2009.12.026
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发表时间：
2010
影响因子：
3.1
通讯作者：
Chin,Khew-Voon
中科院分区：
文献类型：
--
作者：
Yang,Weng-Lang;Ravatn,Roald;Kudoh,Kazuya;Alabanza,Leah;Chin,Khew-Voon
cAMP在细胞中的作用主要由cAMP依赖性蛋白激酶（PKA）介导，PKA由两个遗传上不同的亚基组成，催化亚基（C）和调节亚基（R），形成四聚体全酶R2 C2。R亚基的唯一已知功能是抑制C亚基激酶的活性。研究表明，RIα的过度表达与肿瘤转化相关，而C亚基激酶的过度表达与肿瘤转化无关。此外，研究还表明RIα亚基突变而非C亚基突变与对DNA损伤性抗癌药物顺铂的耐药性增加相关，因此提示PKA的RIα亚基可能具有独立于激酶的功能。我们发现RIα亚基与BTB/POZ结构域锌指转录因子PATZ 1（ZNF 278）相互作用，并与RIα共表达导致其在细胞质中隔离。cAMP可诱导胞质/核易位。C-末端缺失消除了PATZ 1与RIα的相互作用，并导致其定位于细胞核中。PATZ 1反式激活cMyc启动子，cAMP的存在以及与RIα的共表达调节其反式激活。此外，PATZ 1在癌症中异常表达。综上所述，我们的研究结果显示了一种潜在的新机制，即通过RIα与PATZ 1的相互作用介导的cAMP信号转导，该机制不依赖于PKA的激酶活性，并且PATZ 1在癌症中的异常表达表明其在细胞生长调节中的作用。
The effects of cAMP in cell are predominantly mediated by the cAMP-dependent protein kinase (PKA), which is composed of two genetically distinct subunits, catalytic (C) and regulatory (R), forming a tetrameric holoenzyme R2C2. The only known function for the R subunit is that of inhibiting the activity of the C subunit kinase. It has been shown that overexpression of RIα, but not the C subunit kinase, is associated with neoplastic transformation. In addition, it has also been demonstrated that mutation in the RIα, but not the C subunit is associated with increased resistance to the DNA-damaging anticancer drug cisplatin, thus suggesting that the RIα subunit of PKA may have functions independent of the kinase. We show here that the RIα subunit interacts with a BTB/POZ domain zinc-finger transcription factor, PATZ1 (ZNF278), and co-expression with RIα results in its sequestration in the cytoplasm. The cytoplasmic/nuclear translocation is inducible by cAMP. C-terminus deletion abolishes PATZ1 interaction with RIα and results in its localization in the nucleus. PATZ1 transactivates the cMyc promoter and the presence of cAMP and co-expression with RIα modulates its transactivation. Moreover, PATZ1 is aberrantly expressed in cancer. Taken together, our results showed a potentially novel mechanism of cAMP signaling mediated through the interaction of RIα with PATZ1 that is independent of the kinase activity of PKA, and the aberrant expression of PATZ1 in cancer point to its role in cell growth regulation.