A novel mechanism of cell growth regulation by Cell Cycle and Apoptosis Regulatory Protein (CARP)-1.

Q2 Biochemistry, Genetics and Molecular Biology

Journal of Molecular Signaling Pub Date : 2010-07-01 DOI:10.1186/1750-2187-5-7

Yan Jiang, Vineshkumar T Puliyappadamba, Liyue Zhang, Wenjuan Wu, Anil Wali, Michael B Yaffe, Joseph A Fontana, Arun K Rishi

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引用次数: 21

Abstract

Background: CARP-1/CCAR1, a perinuclear phospho-protein, regulates signaling by adriamycin, steroids, or growth factors. However, intracellular events that regulate CARP-1-dependent cell growth are not fully understood.

Results: Here we investigated whether CARP-1 is involved in signaling induced by the protein kinase A inhibitor H89. Treatments of human breast cancer cells with H89 resulted in apoptosis that involved enhanced CARP-1 threonine phosphorylation and expression. Depletion of CARP-1, on the other hand, abrogates apoptosis induced by H89. CARP-1 binds with signal transducer TAZ and over-expression of TAZ inhibits apoptosis by CARP-1. CARP-1 (651-759) interacts with a novel, N-terminal epitope of TAZ. H89 treatment stimulates threonine phosphorylation of CARP-1 (651-759), while substitution of threonine667 to alanine interferes with its binding with TAZ and apoptosis by H89. In addition, expression of wild type or CARP-1 (651-759) causes loss of c-myc expression due, in part, to suppression of c-myc transcription.

Conclusions: CARP-1 threonine667 regulates H89-dependent signaling by a novel pathway that involves modulation of CARP-1 interaction with TAZ and transcriptional down-regulation of c-myc.

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细胞周期与凋亡调节蛋白(CARP)-1调控细胞生长的新机制

背景:CARP-1/CCAR1是一种核周磷酸化蛋白，通过阿霉素、类固醇或生长因子调节信号传导。然而，调节carp -1依赖性细胞生长的细胞内事件尚不完全清楚。结果:我们研究了CARP-1是否参与了蛋白激酶A抑制剂H89诱导的信号传导。用H89处理人乳腺癌细胞可导致细胞凋亡，其中CARP-1苏氨酸磷酸化和表达增强。另一方面，CARP-1的缺失可以消除H89诱导的细胞凋亡。CARP-1与信号传感器TAZ结合，过表达TAZ可通过CARP-1抑制细胞凋亡。CARP-1(651-759)与TAZ的一个新的n端表位相互作用。H89处理刺激CARP-1的苏氨酸磷酸化(651-759)，而苏氨酸667被丙氨酸取代会干扰其与TAZ的结合和H89的凋亡。此外，野生型或CARP-1(651-759)的表达导致c-myc表达缺失，部分原因是c-myc转录受到抑制。结论:CARP-1苏氨酸667通过调节CARP-1与TAZ的相互作用和c-myc的转录下调的新途径调节h89依赖性信号。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Molecular Signaling Biochemistry, Genetics and Molecular Biology-Biochemistry

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期刊介绍： Journal of Molecular Signaling is an open access, peer-reviewed online journal that encompasses all aspects of molecular signaling. Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. Specifically, the research area of the journal is on the normal or aberrant molecular mechanisms involving receptors, G-proteins, kinases, phosphatases, and transcription factors in regulating cell proliferation, differentiation, apoptosis, and oncogenesis in mammalian cells. This area also covers the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological conditions.