Function of MEF2 in T lymphocytes.
Myocyte enhancer factors 2 (MEF2) is a family of
muscle-enriched transcription factors that have an essential role in myogenesis. In
addition, MEF2 is also expressed at high levels in neurons
and lymphocytes, where it serves as a regulator of neuronal and immune cell
differentiation and function [1], [2].
MEF2 is necessary for the transcriptional activation of
Interleukin 2 (IL-2) (and possible other cytokines) during
peripheral T cell activation [3]. It plays a crucial role in T-lymphocyte
apoptosis by regulating expression of Nuclear receptor subfamily 4, group A, member 1
(NUR77) [4], [5].
To date, four MEF2 proteins have been identified:
MEF2A, MEF2B,
MEF2C, and MEF2D, which are
expressed in distinct, but overlapping patterns during embryogenesis, and in adult
tissues. MEF2 proteins form homo- and heterodimers that
constitutively bind to response elements [2].
In T lymphocytes, MEF2 activity is subjected to complex
levels of regulation. MEF2 associates 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)), Myogenic differentiation 1
(MYOD), 14-3-3,
Mitogen-activated protein kinase 7 (ERK5 (MAPK7)),
Calcineurin binding protein 1 (CABIN1), Histone deacetylases
4, 5 7 and 9 (HDAC4, HDAC5,
HDAC7, HDAC9) and is regulated
by MAP kinase cascades and calcium signaling.
Calcium regulates MEF2 activity by three different
mechanisms: via Calcium/calmodulin-dependent protein kinases
(CaMKK), NF-AT1(NFATC2) and
CABIN1.
Association of MEF2 with
HDAC4, HDAC5,
HDAC7 and HDAC9 results in
deacetylation of nucleosomal histones surrounding MEF2
DNA-binding sites, with subsequent suppression of
MEF2-dependent genes. Calcium/calmodulin-dependent protein
kinases I and IV (CaMK I and CaMK
IV) phosphorylate HDACs, creating docking
sites for a 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 is
bound by the p300 co-activator [2].
Calcium-bound Calmodulin 2 (Calmodulin) also associates
with and activates Protein phosphatase 3 (formerly 2B), catalytic subunits
(Calcineurin A (catalytic)). Calcineurin A
(catalytic) dephosphorylates NF-AT1(NFATC2)
leading to its translocation into the nucleus. In the nucleus
NF-AT1(NFATC2) directly associates with
MEF2A and MEF2D and recruits
p300 co-activator to MEF2
target genes [2]. Upon T cell activation, a subpopulation of
Calcineurin A (catalytic) translocates into the nucleus to
maintain the transcriptional activity of NF-AT1(NFATC2) and
other factors [6].
Additionally, MEF2 can associate with
CABIN1, which recruits Histone deacetylases 1 and 2
(HDAC1, HDAC2) via SIN3 homolog A, transcription regulator
(Sin3A) co-repressor, resulting in deacetylation of local
histones and repression of MEF2 target gene transcription
[4].
In response to increased intracellular Ca('2+),
Calmodulin is activated and associated with the
MEF2-binding region of CABIN1,
releasing MEF2 so that it can associate with
NF-AT1(NFATC2)-p300 complexes
and activate target gene expression.
CABIN1 also associates with and represses
Calcineurin A (catalytic), and thus inhibits
MEF2 activity by inhibiting an upstream activator of
MEF2-dependent transcription.
T cell receptor alpha/ beta (TCR
alpha/beta) signaling pathway is known to be down-regulated in the course
of T cell activation [6] CABIN1 was hypothesized
to function in down-modulating TCR alpha/beta signaling via
Calcineurin A (catalytic) activity [4], [5].
Protein kinase C (PKC) activation leads to
hyperphosphorylation of CABIN1, which appears to be required
for its high-affinity interaction with Calcineurin A (catalytic)
[6].
p300 and PCAF
are histone acetyltransferases (HATs). They acetylate histone tails, relaxing chromatin
surrounding MEF2 target sites, with subsequent stimulation
of transcription of MEF2 target gene [2].
MAPKs couple MEF2 to multiple signaling pathways for 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 and
ERK5 (MAPK7) is capable of phosphorylating and activating
MEF2A, MEF2C and
MEF2D [7], [8].
ERK5 (MAPK7) can also function as a transcriptional
co-activator by recruiting basal transcriptional machinery [2].
ERK5 (MAPK7), itself is phosphorylated and activated by
Mitogen-activated protein kinase kinase kinase2 and 3 (MAP3K2
(MEKK2) and MAP2K3) [9].
In response to p38alpha
(MAPK14), p38beta (MAPK11) and
ERK5(MAPK7) MEF2 activates the
transcription factor Jun oncogene (c-Jun), which
participates in regulation of proliferation [2], [10], [11].
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