Discovery of Serum Response Factor (SRF)
In 1984, Greenberg at Harvard University in Boston discovered that serum addition
to quiescent cells in culture could rapidly stimulate
c-fos gene transcription
(1). The induction reached maximum within 15 min and the
c-fos mRNA level
peaked at about 30 min after serum stimulation. This phenomenon led to a series
of important discoveries in the area of gene transcription regulation.
c-fos
is a cellular homolog of the FBJ murine osteosarcoma virus transforming gene
v-fos. Since it is rapidly activated without a need of new protein synthesis,
c-fos was classified as an immediate early gene. Its activation is required
for cells, which have exited the cell cycle, to reenter G1 phase of cell cycle
and subsequently enter mitosis. Later, it was discovered that in addition to
serum, growth factors and other mitogens could activate
c-fos (2). Subsequent
research has focused on the signaling upstream of
c-fos gene and was
aimed to explain why serum could activate
c-fos. Several DNA elements
have been identified in the
c-fos promoter region (3-6), but a particular
attention was given to a short sequence located about 300bp upstream of the
transcription initiation start site. Treisman named this sequence Serum Response
Element (SRE). It is an A/T rich core flanked by an inverted repeat, CCATATTAGG.
This element was necessary and sufficient to render a heterologous promoter
responsive to serum. Comparison of this element with the cytoskeletal actin
gene promoter revealed a similar sequence (7). To date, about 30 genes have
been identified that contain CC(A/T)6GG sequence in their promoter regions (8,
9) (
Table 1). These genes include many immediate early genes such as
c-fos,
fosB,
junB,
egy-1,
egy-2, etc. neuronal
genes such as nur77, nurr1, etc. and muscle genes such as skeletal alpha-actin,
alpha-myosin heavy chain (alpha-MHC), ß-myosin heavy chain (ß-MHC),
myosin light chain (MLC), SM22alpha, telokin, troponin, tropomyosin, calponin,
atrial natriuretic factor (ANF), Sarcoplasmic reticulum Ca2
+-ATPase
(SERCA), dystrophin, creatine kinase M, etc. Because of its special DNA sequence
structure, SRE element is also referred to as CArG box. Treisman also identified
the transcription factor, protein that binds to this element to control particular
gene expression, and he named this protein Serum Response Factor (SRF).
What is SRF?
In humans, SRF gene is located on chromosome 6p21.1, and is 10607 base pair
(bp) long. It contains 7 exons. The full length of its mRNA is 4201bp, exon1
(1-871), exon2 (872-1138), exon3 (1139-1400), exon4 (1401-1520), exon5 (1521-1712),
exon6 (1713-1789), exon7 (1790-4201) (
Fig. 1). The coding region is from
359 to 1885. By alternative splicing, several RNA transcripts could be generated.
Conventionally, two mRNA species, 4.5kb and 2.5kb have been distinguished by
Northern hybridization. In mouse, it has been reported that four RNA isoforms
could be identified, depending on tissue type (10). Among these four isoforms,
SRF-L contained all 7 exons, corresponding to the 4.5kb species in human. SRF-M
isoform was lacking exon5 and functioned as a dominant negative mutant, which
repressed SRF-dependent transcription (11). SRF-S lacking both exon5 and exon4
was only identified in the aorta. SRF-I isoform was the shortest one, contained
only exons1, 2, 6 and 7, and was only detected in embryonic tissues.
Table
1. Genes with SRF binding sites |
Gene |
Function |
Reference |
c-fos |
Proto-oncogene |
Treisman, 1986 (3) |
fosB |
Proto-oncogene |
Lazo et al., 1992 (33) |
junB |
Proto-oncogene |
Perez-Albuerne et al., 1993 (34) |
HSP70 |
Heat shock protein |
Wu et al., 1987 (35) |
egy-1 |
Early growth response |
Qureshi et al., 1991 (36) |
egy-2 (Krox20) |
Early growth response |
Gius et al., 1990 (37) |
Cyr61 |
Cell proliferation |
Latinkic et al., 1991 (38) |
Pip92 |
extracellular signal response |
Chung et al., 1998 (39) |
ß-actin |
Non-muscle actin |
Ng et al., 1989 (40) |
thrombospondin-1 |
angiogenic inhibitor |
Framson and Bornstein, 1993 (41) |
vinculin |
focal adhesion protein |
Moiseyeva et al., 1993 (42) |
IL-2Ralpha |
T cell growth |
Tan et al., 1992 (43) |
Nurr1 (NR4A2) |
orphan nuclear receptor |
Castillo et al., 1997 (44) |
Nur77 (NR4A1) |
orphan nuclear receptor |
Williams and Lau, 1993 (45) |
Cardiac alpha-actin |
Muscle contraction |
Miwa and Kedes, 1987 (46) |
Skeletal alpha-actin |
Muscle contraction |
Muscat et al., 1988 (47) |
Smooth muscle -actin |
Smooth muscle differentiation |
Carson et al., 2000 (48) |
smooth muscle alpha-actin |
Muscle contraction |
Kim et al., 1994 (49) |
alpha-MHC |
Muscle contraction |
Molkentin et al., 1996 (50) |
ß-MHC |
Muscle contraction |
Huang et al., 1997 (51) |
MLC |
Muscle contraction |
Henderson et al., 1989 (52) |
smMHC |
Muscle contraction |
Katoh et al., 1994 (53) |
SM22alpha |
Smooth muscle cell differentiation |
Yamamura et al., 1997 (54) |
telokin |
myosin stabilization |
Herring and Smith, 1997 (55) |
Troponin T |
actin stabilization and modulation |
Wang et al., 1994 (56) |
tropomyosin |
actin stabilization and modulation |
Toutant et al., 1994 (57) |
calponin |
Actin-binding protein |
Miano et al., 2000 (58) |
ANF |
regulation of hydromineral
homeostasis in atria |
Sprenkle et al., 1995 (59) |
SERCA |
Cellular Ca++ level modulation |
Baker et al., 1998 (60) |
dystrophin |
Duchenne muscular dystrophy |
Klamut et al., 1990 (61) |
creatine kinase M |
Muscle contraction |
Vincent et al., 1993 (62) |
|
|
Fig
.1. Diagrammatic presentation of SRF gene structure and alternative splicing.
SRF gene contains seven exons. Four mRNA isoforms have been identified
by RT-PCR and three protein species have been identified by Western blotting. |
SRF protein contains 508 amino acids and is visualized as a 67kDa band on Western
blot. It contains three major domains: (1) a SRE DNA binding domain; (2) a transactivation
domain; and (3) several phosphorylation sites. Deletion analysis identified
the DNA binding and dimerization domain to the region between amino acids 133
and 222 (12). This 90-amino-acid core domain is sufficient for DNA binding,
dimerization and interaction with the accessory factors. This domain is highly
conserved among eukaryotes. Even in those evolutionarily divergent species such
as yeasts and plants an extensive homology has been recognized. This region
is designated the MADS box, standing for MCM-1 from yeasts (13), Agamous and
Deficiens from plants (14), and SRF from animals. Even between fruit fly and
human, there is a 93% homology in SRF (15). The transcription activation domain
is located in the C-terminal region of the SRF protein, within amino acids 339
to 508 region (16).
Biological Functions of SRF
SRF is an important regulator of numerous genes associated with cell growth
and differentiation. SRF also regulates transcription resulting from treatment
of cells with neurotrophins (17), neurotransmitters and agents that raise intracellular
calcium levels (18, 19), stress agents, and viral activators (20, 21). Therefore,
identification of the mechanism by which SRF mediates the activation of genes
and regulation of the SRF gene itself is important for understanding these processes.
Inhibition of SRF by microinjection of anti-SRF antibodies or the expression
of antisense SRF RNA suppressed muscle marker gene expression and blocked the
differentiation of myoblasts to myotubes (22, 23). Moreover, SRF gene knockout
demonstrated that homozygous SRF-/- mouse embryos failed to develop mesoderm
(9). Mouse embryos lacking SRF developed normally until day E6.5. However, the
mesodermal germ layer did not form and as a result, SRF-negative embryos died
in utero between age E8.5 and E12.5. The fact that srf-/- embryos developed
normally up to E6.5 and continued to grow even in the absence of mesoderm suggests
that SRF is not a condition sine qua non for normal cell proliferation. In vitro
study also supports this notion (24). By specific cardiac SRF transgenesis,
we found that overexpression of SRF caused hypertrophic cardiomyopathy in mouse
and the mouse died of heart failure within 6 months after birth (25). Overexpression
of a mutant SRF that has no DNA binding activity severely damaged either embryogenesis
or early development of the mouse, depending on the transgene copy number (26).
On the other hand, overexpression of antisense SRF gave the mouse a better cardiac
performance (Chai
et al., unpublished data). All these transgenic data suggest
that sufficient SRF is needed for embryogenesis and early development. For adults,
maintaining relatively low level of SRF is more beneficial (
Fig. 2).
|
Fig. 2. Western blots showing
overexpression of SRF (upper) and SRF mutant (mSRF) (lower) in transgenic
mice compared to normal ones (25, 26). |
Studies performed on transgenic mice with different CArG boxes with flanking
sequences linked to lacZ (27) suggest that sequences immediately surrounding
the CArG box determine the expression pattern and that CArG boxes with muscle
specificity bind SRF with reduced affinity compared with those with direct ubiquitous
expression.
Activation and Regulation of SRF
SRF can be activated by a variety of agents, including serum, lysophosphatidic
acid (LPA), anisomysin, mitogens, lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate
(TPA), redox, cytokines, tumor necrosis factor-a (TNFa); agents that elevate
intracellular calcium levels; viral activator proteins such as the human T-cell
lymphotropic virus type-1 activator protein Tax-1 and the hepatitis B virus
activator protein pX; activated oncogenes including v-src, v-fps, v-ras, and
the activated proto-oncogene c-raf as well as extracellular stimuli such as
antioxidants, UV light, and microgravity. SRF is regulated both by cellular
signal transduction pathways and by its interaction with other transcription
factors including Sp1, ATF6, GATA4, Nkx2.5, and myogenic regulatory factors.
Several mechanisms have been shown to regulate SRF activity, including (a) association
with positive and negative cofactors (28), (b) phosphorylation-dependent changes
in DNA binding (29), (c) alternative RNA splicing (10, 11), and regulated nuclear
translocation (30).
There are two general classes of signaling mechanisms involving the SRF regulating
SRE activity. A ternary complex factors (TCF)-dependent pathway involves the
ras-raf-MAPK-ERK cascade (31). Both phosphorylation of TCFs and the binding
of TCFs to SRF are required for activation of the SRE by this pathway. A TCF-independent
pathway involves the Rho family of GTPases (32). Several MAPK pathways have
been found to activate TCF. Among them, the extracellular-signal regulated kinase
(ERK) can be activated by the extracellular stimulations mentioned above to
phosphorylate TCF via Ras-Raf-MEK1/MEK2. The Jun N-terminal kinases (JNKs),
also known as stress-activated protein kinases (SAPKs), can be turned on by
cellular stress such as heat or UV light through small GTPases such as Rac and
Cdc42 to phosphorylate TCF. Another subfamily of MAPK, p38/Mpk2/RK, could be
also involved in the TCF activation. On the other hand, the biochemistry of
SRF activation and the signaling pathways still remain unclear. It was recognized
that all the factors that stimulate SRF expression have ability to activate
the small GTPase RhoA. Therefore, it has been proposed that this might be the
path how SRF is triggered. Ca2
+/calmodulin-dependent
kinase (Cam) might be involved in the process of SRF activation by cytoplasmic
Ca2
+ elevation (Fig.3).
Potential Implications for Tissue Injury Healing
As described above, genes under SRF regulation are mainly classified into three
groups: immediate early genes, muscle genes and neuronal genes. Many of them
are involved in cellular response to growth factor stimulation and tissue injury.
Since SRF is an important regulator of these genes involved in cell growth and
differentiation one of its important functions may be involvement in tissue
injury and gastrointestinal ulcer healing. Since gastrointestinal injury is
usually associated with the destruction of epithelium, smooth muscle structures
and neural network and the healing process requires activation of numerous growth
factors, it is reasonable to speculate that SRF might play an important role
in gastrointestinal recovery from various injuries. Healing of these injuries
requires regeneration of epithelial, muscle and neural structures and the neural/brain
– gut interactions play important role in gastrointestinal mucosal and pancreatic
function, defense repair and healing (63-68).
Support: This work was supported by the VA Medical
Research Service, REAP and VA Merit Review Awards A.S.T. Dr J. Chai is an Associate
Investigator in the Research Enhancement Award Program at the VA Medical Center
in Long Beach.
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