Development Role of HDAC and calcium/calmodulin-dependent kinase (CaMK) in control of skeletal myogenesis
Role of HDAC and calcium/calmodulin-dependent kinase (CaMK) incontrol of skeletal myogenesis
There are two families of transcription factors that play pivotal rolesduring mammalian skeletal muscle differentiation. One of them includes MyoD familyproteins (also called myogenic regulatory factors or MRFs), with four members Myf5,Myogenic differentiation 1 ( MYOD ), Myogenin ( MYOG ), and Myogenic factor6 ( MYF6 ) that are exclusively expressed in skeletal muscles. The other groupconsists of Myocyte enhancer factors 2 ( MEF2 ): MEF2A, MEF2B,MEF2C, and MEF2D. The latter can form homo- and heterodimers thatconstitutively bind to the promoters or enhancers of the majority of the muscle-specificgenes. Additionally, MRF and MEF2 members can physically interact with each other tosynergistically activate many muscle-specific genes [1], [2].
The MEF2 activity is subjected to the complex regulation. MEF2 associatewith a variety of regulating proteins: K(lysine) acetyltransferase 2B ( PCAF ),Binding protein p300 ( p300 ), Nuclear factor of activated T-cells, cytoplasmic,calcineurin-dependent 2 ( NF-AT1(NFATC2) ), Nuclear receptor coactivator 2 (NCOA2 (GRIP1/TIF2) ), MYOD, 14-3-3, Mitogen-activated proteinkinase 7 ( ERK5 (MAPK7) ), Histone deacetylases 4, 5 7 and 9 ( HDAC4,HDAC5, HDAC7, HDAC9 ). It is regulated by the MAP kinase cascadesand calcium signaling.
Association of MEF2 with HDAC4, HDAC5, HDAC7 andHDAC9 results in deacetylation of nucleosomal histones surrounding MEF2DNA-binding sites leading to subsequent suppression of MEF2 -dependent genes.Calcium/calmodulin-dependent protein kinase IV ( CaMK IV ) phosphorylatesHDACs and creates docking sites for the chaperone protein 14-3-3. Uponbinding of 14-3-3, HDACs are released from MEF2 and transported(except HDAC9 ) to the cytoplasm via a C-terminal nuclear export sequence. Oncereleased from associated repressors, MEF2 binds the p300 co-activator[2].
The calcium-bound Calmodulin 2 ( Calmodulin ) also binds toProtein phosphatase 3 (formerly 2B), catalytic subunits ( Calcineurin A(catalytic) ) and activates it. Calcineurin A (catalytic) dephosphorylates theNFAT family of transcription factors, leading to their translocation to the nucleus. Inthe nucleus, the NF-AT1(NFATC2) directly associates with MEF2A andMEF2D and recruits the p300 co-activator to MEF2 target genes.[2].
p300 and PCAF are histone acetyltransferases (HATs). Theyacetylate histone tails. This leads to relaxation of the chromatin surroundingMEF2 target sites and subsequent stimulation of MEF2 target genes [2].
MAPK s couple MEF2 to multiple signaling pathways involved in the cellgrowth and differentiation. It was shown that Mitogen activated protein kinases 14 and 11( p38alpha (MAPK14), p38beta (MAPK11) ) phosphorylate and activate MEF2Aand MEF2C, whereas ERK5(MAPK7) can phosphorylate and activate MEF2A, MEF2C and MEF2D [3], [4].
ERK5(MAPK7) can also function as a transcriptional co-activatorby recruiting basal transcriptional machinery [2]. ERK5(MAPK7) inturn is phosphorylated and activated by Mitogen-activated protein kinase kinase kinase2and 3 ( MAP3K2 (MEKK2) and MAP2K3 ) [5].
Two members of the MRFs family are shown to be target genes ofMEF2. These targer proteins are MYF6, MYOG, and muscle-specificenzymes Carnitine palmitoyltransferase 1B ( CPT-1B ) and, possibly, Adenosinemonophosphate deaminase 1 ( AMP deaminase 1 ) and Phosphoglycerate mutase 2 (PGAM2 ) [6], [7], [8], [9],[10].
Additionally, in response to p38alpha (MAPK14), p38beta (MAPK11)and ERK5(MAPK7) MEF2 activates the transcription factor Jun oncogene (c-Jun ) involved in the control of duration of the myoblast proliferation [11], [12].
MYOD, a- coactivator of MEF2, besides activatingmuscle-specific transcription, induces permanent cell cycle arrest by up-regulatingCyclin-dependent kinase inhibitor 1A ( p21 ) [13].
Insulin-like growth factors ( IGF s) were shown to stimulatemyogenesis in addition to extracellular stimuli that lead to activation of MEF2via p38alpha (MAPK14), p38beta (MAPK11) and ERK5(MAPK7) kinase. It has beendemonstrated that Phosphoinositide-3-kinase ( PI3K ) mediates the stimulatoryeffect of IGFs in muscle differentiation. PI3K convertsphosphatidylinositol 4,5-bisphosphate ( PtdIns(4,5)P2 ) to phosphatidylinositol3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ), therefore leading to activation of the3-phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) )and v-akt murinethymoma viral oncogene homolog ( AKT(PKB) ). AKT(PKB) activatestranscription MYOG via Ribosomal protein S6 kinase, 70kDa, polypeptide 1 ( p70S6 kinase1 ), but exact mechanism of this regulation is not known [1].
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