Role of HDAC and calcium/calmodulin-dependent kinase
(CaMK) in control of skeletal myogenesis
There are two families of transcription factors that play pivotal roles
during mammalian skeletal muscle differentiation. One of them includes MyoD family
proteins (also called myogenic regulatory factors or MRFs), with four members Myf5,
Myogenic differentiation 1 (MYOD), Myogenin
(MYOG), and Myogenic factor 6
(MYF6) that are exclusively expressed in skeletal muscles.
The other group consists of Myocyte enhancer factors 2
MEF2B, MEF2C, and
MEF2D. The latter can form homo- and heterodimers that
constitutively bind to the promoters or enhancers of the majority of the muscle-specific
genes. Additionally, MRF and MEF2 members can physically interact with each other to
synergistically activate many muscle-specific genes , .
The MEF2 activity is subjected to the complex regulation.
MEF2 associate with 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
protein kinase 7 (ERK5 (MAPK7)), Histone deacetylases 4, 5 7
and 9 (HDAC4, HDAC5,
HDAC7, HDAC9). It is regulated
by the MAP kinase cascades and calcium signaling.
Association of MEF2 with
HDAC4, HDAC5, HDAC7 and
HDAC9 results in deacetylation of nucleosomal histones
surrounding MEF2 DNA-binding sites leading to subsequent
suppression of MEF2-dependent genes.
Calcium/calmodulin-dependent protein kinase IV (CaMK IV)
phosphorylates HDACs and creates docking sites for the
chaperone protein 14-3-3. Upon binding of
14-3-3, HDACs are released from
MEF2 and transported (except
HDAC9) to the cytoplasm via a C-terminal nuclear export
sequence. Once released from associated repressors, MEF2
binds the p300 co-activator .
The calcium-bound Calmodulin 2
(Calmodulin) also binds to Protein phosphatase 3 (formerly
2B), catalytic subunits (Calcineurin A (catalytic)) and
activates it. Calcineurin A (catalytic) dephosphorylates the
NFAT family of transcription factors, leading to their translocation to the nucleus. In
the nucleus, the NF-AT1(NFATC2) directly associates with
MEF2A and MEF2D and recruits
the p300 co-activator to MEF2
p300 and PCAF
are histone acetyltransferases (HATs). They acetylate histone tails. This leads to
relaxation of the chromatin surrounding MEF2 target sites
and subsequent stimulation of MEF2 target genes .
MAPKs couple MEF2 to
multiple signaling pathways involved in the cell growth and differentiation. It was shown
that Mitogen activated protein kinases 14 and 11 (p38alpha (MAPK14),
p38beta (MAPK11)) phosphorylate and activate
MEF2A and MEF2C, whereas
ERK5(MAPK7) can phosphorylate and activate
MEF2A, MEF2C and
MEF2D , .
ERK5(MAPK7) can also function as a
transcriptional co-activator by recruiting basal transcriptional machinery . ERK5(MAPK7) in turn is phosphorylated and
activated by Mitogen-activated protein kinase kinase kinase2 and 3 (MAP3K2
(MEKK2) and MAP2K3) .
Two members of the MRFs family are shown to be target genes of
MEF2. These targer proteins are
MYF6, MYOG, and muscle-specific
enzymes Carnitine palmitoyltransferase 1B (CPT-1B) and,
possibly, Adenosine monophosphate deaminase 1 (AMP deaminase
1) and Phosphoglycerate mutase 2 (PGAM2)
, , , , .
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 , .
MYOD, a- coactivator of
MEF2, besides activating muscle-specific transcription,
induces permanent cell cycle arrest by up-regulating Cyclin-dependent kinase inhibitor 1A
Insulin-like growth factors (IGFs) were
shown to stimulate myogenesis in addition to extracellular stimuli that lead to
activation of MEF2 via p38alpha (MAPK14),
p38beta (MAPK11) and ERK5(MAPK7) kinase. It
has been demonstrated that Phosphoinositide-3-kinase (PI3K)
mediates the stimulatory effect of IGFs in muscle
differentiation. PI3K converts phosphatidylinositol
4,5-bisphosphate (PtdIns(4,5)P2) to phosphatidylinositol
3,4,5-trisphosphate (PtdIns(3,4,5)P3), therefore leading to
activation of the 3-phosphoinositide dependent protein kinase-1 (PDK
(PDPK1))and v-akt murine thymoma viral oncogene homolog
(AKT(PKB)). AKT(PKB) activates
transcription MYOG via Ribosomal protein S6 kinase, 70kDa,
polypeptide 1 (p70 S6 kinase1), but exact mechanism of this
regulation is not known .
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