Abstract:
:The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has been proposed to fulfill a negative feedback loop that restrains potentially pathological calcineurin signaling, which would otherwise lead to abnormal cardiac growth. In a high-throughput screen for small molecules capable of regulating MCIP1 expression in muscle cells, we identified a unique 4-aminopyridine derivative exhibiting an embedded partial structural motif of serotonin (5-hydroxytryptamine, 5-HT). This molecule, referred to as pyridine activator of myocyte hypertrophy, acts as a selective agonist for 5-HT(2A/2B) receptors and induces hypertrophy of cardiac muscle cells through a signaling pathway involving calcineurin and a kinase-dependent mechanism that inactivates class II histone deacetylases, which act as repressors of cardiac growth. These findings identify MCIP1 as a downstream target of 5-HT(2A/2B) receptor signaling in cardiac muscle cells and suggest possible uses for 5-HT(2A/2B) agonists and antagonists as modulators of cardiac growth and gene expression.
journal_name
Proc Natl Acad Sci U S Aauthors
Bush E,Fielitz J,Melvin L,Martinez-Arnold M,McKinsey TA,Plichta R,Olson ENdoi
10.1073/pnas.0308723101keywords:
subject
Has Abstractpub_date
2004-03-02 00:00:00pages
2870-5issue
9eissn
0027-8424issn
1091-6490pii
0308723101journal_volume
101pub_type
杂志文章abstract::The tumor suppressor Smad4/Dpc4 is a transcription activator that binds specific DNA sequences and whose nuclear localization is induced after exposure to type beta transforming growth factor-like cytokines. We explored an inducible system in which Smad4 protein is activated by translocation to the nucleus when cell l...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.96.4.1427
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更新日期:2013-01-02 00:00:00
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更新日期:1991-10-01 00:00:00
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pub_type: 临床试验,杂志文章
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更新日期:2014-07-29 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1990-06-01 00:00:00
abstract::Regulated proteolysis is required to execute many cellular programs. In Caulobacter crescentus, timely degradation of the master regulator CtrA by ClpXP protease is essential for cell-cycle progression and requires the colocalization of CtrA and RcdA. Here, we establish a biochemical framework to understand regulated ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2007-04-17 00:00:00