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Promiscuous actions of small molecule inhibitors of the protein kinase D‐class IIa HDAC axis in striated muscle
Author(s) -
Lemon Douglas D.,
Harrison Brooke C.,
Horn Todd R.,
Stratton Matthew S.,
Ferguson Bradley S.,
Wempe Michael F.,
McKinsey Timothy A.
Publication year - 2015
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2015.03.017
Subject(s) - mef2 , kinase , transcription factor , microbiology and biotechnology , phosphorylation , chemistry , protein kinase a , gene , biology , biochemistry , enhancer
PKD‐mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Gö‐6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Gö‐6976 triggered calcium signaling and activated stress‐inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Gö‐6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD.