| 2002 |
BSAC/MKL1 is a nuclear transcriptional activator that potently activates promoters containing CArG boxes (A+T-rich sequences). Both N-terminal basic and C-terminal proline-rich domains are required for transcriptional activity. Overexpression inhibits TNF-induced caspase activation and cell death, with an intimate correlation between transcriptional activity and antiapoptotic function. |
Functional cloning, reporter gene assay, domain deletion mutagenesis, overexpression in DKO MEFs |
The Journal of biological chemistry |
Medium |
12019265
|
| 2004 |
MKL1 functions as a Rho GTPase-regulated coactivator of SRF to drive a subset (~28 of 150) of serum-inducible immediate-early genes; dominant-negative MKL1 specifically blocks the Rho-MKL pathway without affecting TCF/Elk1-dependent SRF targets. |
Microarray expression profiling using dominant-negative MKL1 cell line, promoter analysis |
BMC molecular biology |
Medium |
15329155
|
| 2005 |
MKL1 is covalently modified by SUMO-1 at lysine residues K499, K576, and K624. SUMOylation is enhanced by serum stimulation or constitutively active RhoA. Mutation of these three sites strongly enhances MKL1 transcriptional activity without affecting MKL1-SRF interaction, demonstrating that SUMOylation represses MKL1 transcriptional activity. |
Yeast two-hybrid (identified UBC9), GST pull-down, in vitro SUMOylation reconstitution, site-directed mutagenesis, reporter gene assay |
Genes to cells : devoted to molecular & cellular mechanisms |
High |
16098147
|
| 2006 |
MKL1/Mkl1 is required for physiological preparation of the mammary gland during pregnancy and maintenance of lactation. Mkl1 knockout mice exhibit premature involution and impaired expression of SRF-dependent genes in mammary myoepithelial cells, establishing MKL1 as an essential SRF coactivator in this tissue. |
Gene targeting (Mkl1 knockout mice), histology, gene expression analysis |
Molecular and cellular biology |
High |
16847333
|
| 2006 |
MKL1 and MKL2 regulate expression of CArG-containing smooth muscle marker genes (SM alpha-actin, telokin) but not CArG-independent genes. PDGF-BB causes dissociation of MKL factors from CArG-containing promoters via competition with phospho-Elk-1 and subsequent HDAC2/4/5-mediated reduction of acetylated histone H4, repressing SMC marker genes. |
Gain- and loss-of-function experiments, chromatin immunoprecipitation (ChIP) |
American journal of physiology. Cell physiology |
Medium |
16987998
|
| 2008 |
MKL1 directly activates alpha-smooth muscle actin (alpha-SMA) transcription via CArG elements in renal tubular epithelial cells. MKL1 fused to GFP localizes to the nucleus and induces alpha-SMA expression regardless of TGF-β1. siRNA knockdown of MKL1 abolishes TGF-β1-stimulated alpha-SMA expression. ChIP demonstrates that TGF-β1 induces binding of endogenous SRF and MKL1 to the alpha-SMA promoter. MKL1 expression is regulated by the proteasomal ubiquitin pathway. |
GFP fusion localization, siRNA knockdown, ChIP, reporter gene assay, proteasome inhibitor treatment |
American journal of physiology. Renal physiology |
High |
18337547
|
| 2008 |
The oncogenic OTT-BSAC/MKL1 fusion protein localizes exclusively to the nucleus (unlike BSAC alone which is predominantly cytoplasmic), aberrantly activates promoters containing YY1-binding sequences, and its formation disrupts the interaction between OTT and HDAC3, collectively perturbing normal transcriptional regulation. |
Subcellular localization assay, reporter gene assay, co-immunoprecipitation |
The Journal of biological chemistry |
Medium |
18667423
|
| 2009 |
MKL1 promotes megakaryocytic differentiation by activating SRF. Overexpression of MKL1 increases megakaryocyte number and ploidy; this effect is abrogated by SRF knockdown. Mkl1 knockout mice have reduced platelet counts and reduced megakaryocyte ploidy. |
MKL1 overexpression in HEL cells and primary CD34+ cells, SRF knockdown, Mkl1 knockout mice |
Blood |
High |
19136660
|
| 2010 |
MKL/MRTF family members are found tethered to monomeric actin in the cytoplasm of hippocampal neurons but translocate to the nucleus upon synaptic activation, where they associate with SRF to regulate expression of structural genes. Mkl expression undergoes learning-associated changes in the hippocampus, contributing to two phases of gene regulation during memory consolidation. |
Subcellular localization by immunofluorescence, passive avoidance conditioning, gene expression analysis |
Cerebral cortex (New York, N.Y. : 1991) |
Medium |
20016002
|
| 2010 |
Activin promotes dendritic complexity of cortical neurons in an SRF- and MKL-dependent manner. Activin promotes nuclear export of SCAI (a corepressor of SRF-MKL), and SCAI overexpression blocks activin-induced SRF transcriptional responses and dendritic complexity, identifying an activin-SCAI-MKL signaling axis. |
Neuronal morphology analysis, SCAI overexpression/knockdown, SRF reporter assay, subcellular localization of SCAI |
The Journal of biological chemistry |
Medium |
20709749
|
| 2012 |
MKL1 and MKL2 play redundant roles in megakaryocyte maturation and platelet formation: double-knockout (MKL1/MKL2) megakaryocytes show more severe thrombocytopenia, ploidy reduction, and cytoskeletal/membrane disorganization than single MKL1 KO. Comparison of gene expression in DKO vs. SRF-deficient megakaryocytes reveals ~4400 differentially regulated genes, indicating both SRF-dependent and SRF-independent activities. |
Conditional Mkl2 knockout on Mkl1 KO background (DKO), platelet counting, electron microscopy, immunofluorescence, gene expression comparison with SRF KO |
Blood |
High |
22806889
|
| 2012 |
MRTF-A/MAL promotes expression of adhesive genes (integrin α5, plakophilin 2/Pkp2, FHL1) via the actin-MAL-SRF signaling pathway. Elevated MAL impairs migration of non-invasive cells; knockdown of integrin α5, Pkp2, or FHL1 reverses this anti-migratory effect. ChIP shows inducible MAL/SRF recruitment to regulatory elements of the integrin α5 and Pkp2 genes. |
MAL overexpression and dominant-negative constructs, siRNA knockdown, wound-healing assay, ChIP |
Journal of cell science |
High |
22223881
|
| 2012 |
MRTF-A expression is induced in injured/dedifferentiated vascular smooth muscle cells (VSMCs) and drives pathological vascular remodeling. MRTF-A promotes VSMC migration by activating SRF targets vinculin, MMP-9, and integrin β1. MRTF-A induction in dedifferentiated VSMCs is caused by downregulation of microRNA-1. |
MRTF-A knockout mice (wire injury and ApoE-/- atherosclerosis models), siRNA knockdown in VSMCs, migration assays, CCG1423 pharmacological inhibition |
The EMBO journal |
High |
23103763
|
| 2013 |
Lamin A/C-deficient and Lmna(N195K/N195K) mutant cells have impaired nuclear translocation of MKL1 caused by altered actin dynamics. Ectopic expression of emerin, which is mislocalized in Lmna mutant cells, restores MKL1 nuclear translocation and rescues actin dynamics. This establishes that lamin A/C and emerin regulate MKL1 nucleo-cytoplasmic shuttling through modulation of actin polymerization. |
Live-cell imaging of MKL1 translocation, ectopic emerin expression in Lmna-/- cells, actin dynamics assays |
Nature |
High |
23644458
|
| 2013 |
MKL1 is recruited to the ET-1 promoter by SRF in response to hypoxia in human vascular endothelial cells, where it facilitates histone modifications consistent with transcriptional activation and recruits chromatin remodeling complex components Brg1 and Brm, which are indispensable for ET-1 transactivation. |
ChIP, dominant-negative MKL1, siRNA knockdown, reporter assay |
Nucleic acids research |
High |
23625963
|
| 2013 |
MRTF-A promotes SMYD3-dependent histone methylation on the MYL9 promoter to activate MYL9 transcription and breast cancer cell migration. Co-immunoprecipitation and mutation analysis show that this cooperative transactivation requires the proximal CArG-box binding element of MRTF-A and the HMT activity of SMYD3. |
Co-IP, siRNA knockdown, reporter gene assay with promoter mutation, cell migration assay, ChIP |
Cancer letters |
Medium |
24189459
|
| 2013 |
Cell shape regulates MRTF-A subcellular localization during TGF-β1-induced EMT: cell spreading promotes nuclear accumulation of MRTF-A, whereas blocking cell spreading prevents MRTF-A nuclear translocation and the myofibroblast phenotype. Overexpression of MRTF-A promotes cytoskeletal protein expression independent of cell shape. |
Micro-contact printing to control cell shape, pharmacological inhibition of cytoskeletal tension (blebbistatin), MRTF-A overexpression, immunofluorescence |
PloS one |
Medium |
24340092
|
| 2014 |
Induction of adipocyte differentiation disrupts actin stress fibres via RhoA-ROCK downregulation, causing a rapid increase in monomeric G-actin that binds MKL1 and prevents its nuclear translocation, thereby allowing PPARγ expression and adipogenic differentiation. MKL1 and PPARγ act in a mutually antagonistic manner during adipogenic differentiation. |
Actin manipulation (cytochalasin D, latrunculin A), MKL1 overexpression/siRNA, PPARγ reporter assay, Co-IP, subcellular fractionation |
Nature communications |
High |
24569594
|
| 2014 |
Thymosin β4 (Tβ4) induces MRTF-A translocation to the nucleus by binding G-actin, activating SRF and driving CCN1 and CCN2 transcription to promote capillary proliferation and pericyte recruitment, respectively. Loss of MRTF-A/B or CCN1 function abolishes the Tβ4 neovascularization effect. |
Forced MRTF-A expression, MRTF-A/B knockout mice, hindlimb ischemia model, functional assays, nuclear translocation imaging |
Nature communications |
High |
24910328
|
| 2014 |
MRTF-A is recruited to the ET-1 promoter by c-Jun/c-Fos (AP-1) in response to Ang II, where it alters chromatin structure by modulating histone acetylation and H3K4 methylation, driving ET-1 transcription and cardiac hypertrophy. Endothelial-specific MRTF-A silencing phenocopies systemic MRTF-A deletion in Ang II-induced pathological hypertrophy. |
ChIP, MRTF-A overexpression/depletion, lentiviral endothelial-specific silencing, luciferase reporter, co-IP |
Journal of molecular and cellular cardiology |
High |
25446178
|
| 2014 |
MRTF-A and STAT3 physically interact and synergistically activate transcription of migration markers MYL9 and Cyr-61 via CArG box binding, promoting breast cancer cell migration. The RhoA-MRTF-A and JAK-STAT3 pathways cross-talk in this process. |
Co-IP demonstrating physical MRTF-A/STAT3 interaction, reporter assay, siRNA knockdown, migration assay |
Cellular signalling |
Medium |
25038455
|
| 2015 |
Loss-of-function homozygous MKL1 mutation in a human patient causes primary immunodeficiency characterized by loss of F-actin content in immune cells, reduced G-actin levels, and downregulation of multiple actin-regulating genes. MKL1-deficient neutrophils display severely impaired migration and nearly abolished phagocytosis, and primary dendritic cells cannot form podosomes. Myeloid cell silencing experiments confirm that F-actin assembly is abrogated through reduced G-actin levels. |
Patient genetic analysis, flow cytometry (F-actin content), migration assays, phagocytosis assay, siRNA knockdown in myeloid cell lines |
Blood |
High |
26224645
|
| 2015 |
MKL1 promotes lung cancer cell migration and invasion by epigenetically activating MMP9 transcription. MKL1 recruits ASH2 (a component of the H3K4 methyltransferase complex) to the MMP9 promoter, and MKL1 knockdown eliminates H3K4 methylation at the MMP9 promoter. |
ChIP, siRNA knockdown, migration/invasion assays, reporter assay |
Oncogene |
Medium |
25746000
|
| 2015 |
TGF-β induces MKL1 binding to pro-fibrogenic gene promoters. MKL1 promotes the interaction between MKL1 and SMAD3 — each requiring the other for chromatin occupancy. MKL1 recruits a H3K4 methyltransferase complex to fibrogenic promoters, and knockdown of individual complex members reduces SMAD3 binding and portal fibroblast activation. |
ChIP, Co-IP, siRNA knockdown, bile duct ligation mouse model |
Biochimica et biophysica acta |
Medium |
26241940
|
| 2015 |
Filamin A (FLNA) physically interacts with MKL1 via identified interaction domains. FLNA-MKL1 interaction is required for MKL1 target gene expression and cell migration in primary fibroblasts and cancer cells. LPA-induced RhoA activation promotes endogenous MKL1-FLNA association; actin polymerization inhibitors dissociate the complex. An MKL1 mutant unable to bind FLNA shows impaired cell migration and reduced SRF target gene expression, establishing FLNA as a positive transducer linking F-actin to MKL1-SRF activity. |
Co-IP, domain mapping, site-directed mutagenesis, reporter assay, migration assay across multiple cell types |
Science signaling |
High |
26554816
|
| 2015 |
Mkl1 SAP domain-dependent signaling (independent of SRF) mediates aggressive mammary tumor progression following radiotherapy. Application of dynamic strain or matrix stiffness converts predominantly SRF/Mkl1-dependent gene expression to SAP-domain-dependent Mkl1 signaling and promotes SAP-dependent tumor cell migration; tumors expressing Mkl1 lacking the SAP domain exhibit impaired growth and metastasis. |
Tumor overexpression (full-length vs. SAP-deleted Mkl1), in vivo preirradiated mammary gland model, migration assays, transcript profiling |
Molecular oncology |
Medium |
25999144
|
| 2015 |
MKL1 inhibits cell cycle progression in podocytes via transcriptional activation of p21 through a CArG element in the p21 promoter. MKL1 overexpression decreases S-phase cells; knockdown has the opposite effect. ChIP confirms MKL1 recruitment to the p21 promoter. |
MKL1 overexpression and siRNA knockdown, cell cycle analysis (flow cytometry), ChIP, PCR array, reporter assay |
BMC molecular biology |
Medium |
25888165
|
| 2016 |
Rho-dependent MRTF-A phosphorylation reflects relief from inhibitory nuclear actin. Multiple serum-induced S/T-P phosphorylation sites are required for transcriptional activation. ERK-mediated S98 phosphorylation inhibits G-actin complex assembly on the RPEL domain, promoting nuclear import. S33 phosphorylation potentiates an autonomous Crm1-dependent N-terminal NES that cooperates with five other NES elements to exclude MRTF-A from the nucleus. Thus phosphorylation plays both positive and negative roles in MRTF-A regulation. |
Phosphosite mapping (mass spectrometry), site-directed mutagenesis, nuclear localization assays, Crm1 inhibition, in vitro G-actin binding assay |
eLife |
High |
27304076
|
| 2016 |
MRTF-A and STAT3 synergistically recruit DNMT1 to the BRMS1 promoter, causing hypermethylation and transcriptional silencing of BRMS1 to promote breast cancer cell migration. Physical interaction between MRTF-A and STAT3 promotes DNMT1 transactivity by binding to the GAS element in the DNMT1 promoter. |
Luciferase reporter assay, Co-IP, ChIP, bisulfite sequencing, siRNA knockdown, migration assay |
IUBMB life |
Medium |
25854163
|
| 2016 |
MKL regulates cellular levels of profilin isoforms Pfn1 and Pfn2 indirectly through modulation of STAT1, utilizing MKL's SAP domain function independently of SRF. MKL also influences Pfn1 cellular externalization rather than transcription, and modulates cell migration through Pfn1. |
Reporter assay, siRNA knockdown, MKL SAP domain mutants, migration assay, cellular fractionation |
The Journal of biological chemistry |
Medium |
28546428
|
| 2016 |
p38MAPK/MK2 phosphorylates MRTF-A at Ser351 (Ser312 in human) and Ser371 (Ser333 in human) in a stress-dependent (not mitogen-induced) manner. This was confirmed by in vitro kinase assay, phospho-specific antibodies, MK2/3-deficient cells, and phospho-site mutants. However, these phosphorylations do not detectably affect MRTF-A dimerization, subcellular localization, actin interaction, SRF interaction, SMAD3 interaction, or transactivating potential under the tested conditions. |
Phosphoproteomic approaches (two independent), in vitro kinase assay, phospho-site mutagenesis, subcellular localization assay, MK2/3 KO cells |
Scientific reports |
Medium |
27492266
|
| 2016 |
MKL1 independently inhibits brown adipogenesis. MKL1 knockdown induces brown adipocyte differentiation and increases PPARγ target gene expression. Co-IP demonstrates that MKL1 physically interacts with PPARγ, suggesting MKL1 exerts its effect by modulating PPARγ activity independently of its SRF-related function. |
siRNA knockdown, brown adipocyte differentiation assays, Co-IP, UCP1 and thermogenic gene expression |
PloS one |
Medium |
28125644
|
| 2017 |
MKL1 is acetylated in vivo by PCAF (lysine acetyltransferase). Pro-inflammatory stimuli (TNF-α, LPS) augment MKL1 acetylation and promote MKL1 binding to NF-κB target promoters. Acetylation at four conserved lysine residues is required for MKL1 trans-activation of NF-κB target genes. Mechanistically, MKL1 acetylation promotes nuclear enrichment, enhances MKL1-NF-κB interaction, and stabilizes MKL1 binding to target promoters. |
Co-IP (MKL1-PCAF interaction), acetylation assay, site-directed mutagenesis (4 Lys mutant), ChIP, nuclear fractionation, reporter assay |
Biochimica et biophysica acta. Gene regulatory mechanisms |
High |
28571745
|
| 2017 |
MKL1 recruits SET1 (H3K4 methyltransferase) and BRG1 (chromatin remodeler) to the MMP2 promoter via NF-κB in response to hypoxia in ovarian cancer cells, coordinating their interaction to alter chromatin structure and activate MMP2 transcription. This promotes cancer cell migration and invasion. |
ChIP, Co-IP, siRNA knockdown, reporter assay, migration/invasion assay |
Biochemical and biophysical research communications |
Medium |
28385531
|
| 2017 |
WDR1 promotes nuclear import of MRTF-A by affecting expression of the nuclear transport protein importin, enhancing MRTF-A-induced cell migration. MRTF-A in turn promotes miR-206 expression via CArG box in its promoter; miR-206 then inhibits WDR1 and MRTF-A expression, forming a feedback loop regulating breast cancer cell migration. |
siRNA knockdown, nuclear fractionation, importin expression analysis, reporter assay (CArG box), migration assay |
Experimental cell research |
Medium |
28822708
|
| 2018 |
In drug-resistant basal cell carcinomas, nuclear MKL1 forms a protein complex with SRF and GLI1 near hedgehog target genes, amplifying GLI1 transcriptional activity. Cytoskeletal activation through Rho and mDia (formin) is required for SRF-MKL-driven GLI1 activation and tumor cell viability. |
Multidimensional genomics, Co-IP (MKL1-SRF-GLI1 complex), Rho/mDia pathway inhibition, nuclear MKL1 staining as biomarker |
Nature medicine |
High |
29400712
|
| 2018 |
HDAC6 co-immunoprecipitates with MRTF-A and deacetylates it; pharmacological inhibition of HDAC6 with tubastatin A increases MRTF-A acetylation and total MRTF-A protein, enhancing SRF transcriptional activity in vascular smooth muscle cells. |
Co-IP, HDAC6 inhibition (tubastatin A), HDAC6 knockdown, luciferase reporter, in vivo carotid injury model |
JACC. Basic to translational science |
Medium |
30623138
|
| 2018 |
MRTF-A mediates macrophage ROS production during acute kidney injury by promoting NOX1 transcription. Mechanistically, MRTF-A interacts with the acetyltransferase MYST1 to regulate histone H4K16 acetylation at NOX1/NOX4 gene promoters. Macrophage-specific MRTF-A deletion ameliorates AKI in mice. |
Macrophage-specific KO, ChIP, Co-IP (MRTF-A-MYST1), in vitro NOX promoter assay, AKI mouse models |
Biochimica et biophysica acta. Molecular basis of disease |
Medium |
29908908
|
| 2019 |
MKL1 directly binds the CTGF promoter by interacting with SMAD3, activating CTGF transcription in renal tubular epithelial cells. MKL1 mediates interplay between p300 and WDR5 to regulate CTGF transcription. Genetic or pharmacological inhibition of MKL1 reduces renal fibrosis in vivo. |
ChIP, Co-IP (MKL1-SMAD3-p300-WDR5 interactions), UUO mouse model of fibrosis, siRNA knockdown |
Journal of cellular physiology |
Medium |
31637729
|
| 2019 |
The mRNA export factor Ddx19/Dbp5 is specifically required for nuclear import of MKL1. Ddx19 modulates the conformation of MKL1, affecting its interaction with Importin-β for efficient nuclear import. This effect requires RNA binding activity of Ddx19 but not its helicase or nuclear pore-binding activities. |
siRNA knockdown, nuclear localization assay, Co-IP (MKL1-Importin-β), domain mutagenesis of Ddx19, rescue experiments |
Nature communications |
High |
25585691
|
| 2019 |
MRTF-A directly binds the Abl1 (c-Abl) promoter via interaction with Sp1 to activate c-Abl transcription. Reciprocally, c-Abl activates ERK, which phosphorylates MRTF-A and promotes its nuclear translocation, forming a positive feedback loop contributing to hepatic stellate cell activation and liver fibrosis. |
ChIP (MRTF-A binding to Abl1 promoter), Co-IP (MRTF-A-Sp1), pharmacological c-Abl inhibition, nuclear fractionation, MRTF-A KO mice |
Frontiers in cell and developmental biology |
Medium |
31681772
|
| 2019 |
MKL1-actin pathway reduces chromatin accessibility and impedes somatic cell reprogramming to pluripotency. Sustained MKL1 expression yields excessive actin cytoskeleton, decreases nuclear volume, and reduces global chromatin accessibility. This block can be partially bypassed by inhibiting the Sun2-containing LINC complex, linking cytoskeletal tension to chromatin regulation. |
MKL1 overexpression, ATAC-seq (chromatin accessibility), nuclear volume measurement, LINC complex disruption, reprogramming assays |
Nature communications |
High |
30979898
|
| 2019 |
MRTF-A interacts with SRF to bind directly to the EREG promoter and activate EREG transcription in hepatic stellate cells (HSC). EREG stimulation promotes MRTF-A nuclear translocation in HSC, forming a feedforward loop where MRTF-A drives EREG production, and EREG in turn re-activates MRTF-A. |
ChIP, Co-IP (MRTF-A/SRF), MRTF-A KO mice, nuclear fractionation, siRNA knockdown |
Frontiers in cell and developmental biology |
Medium |
33520984
|
| 2020 |
MKL1 deficiency in a second family with homozygous frameshift mutation causes severe neutrophil actin polymerization defect, strongly reduced motility/chemotactic response, and failure of firm adherence and transendothelial migration under flow. Proteomic and transcriptomic analyses confirm actin and actin-related proteins are downregulated in patient neutrophils. Non-hematopoietic primary fibroblasts show defective myofibroblast differentiation but normal migration, attributed to MKL2 compensation. |
Patient genetic analysis, proteomic/transcriptomic analysis, actin polymerization assay, migration/chemotaxis assay, transendothelial migration under flow, degranulation assay |
Blood |
High |
32128589
|
| 2020 |
YAP promotes myofibroblast differentiation in cardiac fibroblasts through TEAD1-driven de novo expression of MRTF-A, which then drives extracellular matrix gene expression. Genetic inhibition of fibroblast YAP attenuates cardiac fibrosis and reduces MRTF-A expression. |
Cardiac fibroblast-specific YAP knockout, gene expression analysis, fibrosis assessment after myocardial infarction |
JACC. Basic to translational science |
Medium |
33015415
|
| 2020 |
MRTF-A interacts with TIP60 acetyltransferase to synergistically activate iNOS transcription in macrophages during hypoxia-reoxygenation. MRTF-A directly binds the iNOS promoter; its binding is associated with trimethylated H3K4, acetylated H3K9, H3K27, and H4K16. TIP60 also forms crosstalk with the H3K4 trimethyltransferase complex at this promoter. |
ChIP (MRTF-A binding to iNOS promoter + histone marks), Co-IP (MRTF-A-TIP60), siRNA knockdown, MRTF-A KO mice |
Frontiers in cell and developmental biology |
Medium |
32626711
|
| 2021 |
TGF-β upregulates MRTF-A expression in non-small-cell lung cancer cells; MRTF-A then interacts with NF-κB/p65 (rather than SRF) to facilitate p65 binding to the PDL1 promoter, activating PD-L1 transcription and promoting immune escape. |
Co-IP (MRTF-A/NF-κB p65), ChIP (p65 binding to PDL1 promoter), siRNA knockdown, reporter assay, syngraft tumor model |
Experimental & molecular medicine |
Medium |
34548615
|
| 2021 |
MKL1 interacts with E2F1 to activate FOXM1 transcription in vascular smooth muscle cells. ROS-induced MKL1 phosphorylation through MK2 is essential for this MKL1-E2F1 interaction and FOXM1 trans-activation. VSMC-specific deletion of MKL1 suppresses neointima formation in mice. |
VSMC-specific MKL1 KO, Co-IP (MKL1-E2F1), ChIP, siRNA knockdown, MK2 inhibition, ROS assays, neointima model |
Redox biology |
Medium |
36587486
|
| 2022 |
In LMNA-mutant muscle cells, ERK1/2-phosphorylated cofilin-1 (pT25-cofilin-1) binds MRTF-A in the cytoplasm, preventing SRF stimulation in the nucleus. MRTF-A/SRF inhibition decreases ATAT1 expression and thus α-tubulin acetylation. In Atat1 KO mice, left ventricular dilation and Cx43 mislocalization are observed. Tubastatin A treatment restores Cx43 localization and cardiac function in Lmna mutant mice. |
Co-IP (cofilin-1/MRTF-A interaction), cardiomyocytes from LMNA patient-derived iPSCs, Lmna(H222P/H222P) mice, Atat1 KO mice, tubastatin A treatment, cardiac functional assessment |
Nature communications |
High |
36550158
|
| 2023 |
The lncRNA INKILN physically interacts with MKL1 to stabilize it and reduces MKL1 ubiquitination by protecting the physical interaction between MKL1 and the deubiquitinase USP10. INKILN depletion abolishes the physical interaction between p65 and MKL1 and blocks interleukin-1β-induced nuclear localization of both p65 and MKL1, reducing NF-κB-driven vascular smooth muscle inflammation. |
RNA-protein interaction assays, Co-IP (INKILN/MKL1/USP10/p65 interactions), MKL1 ubiquitination assay, siRNA knockdown, BAC transgenic mice, NF-κB reporter |
Circulation |
High |
37199168
|
| 2023 |
MRTF-A interacts with TEAD1 to bind the Zeb1 promoter and activate Zeb1 transcription in renal fibroblasts. Zeb1 in turn represses IRF9 transcription, promoting fibroblast-to-myofibroblast transition. Myofibroblast-specific deletion of MRTF-A ameliorates renal fibrosis. |
ChIP (MRTF-A/TEAD1 at Zeb1 promoter), Co-IP, siRNA knockdown, Postn-CreERT2 x Mrtfa-flox conditional KO mice, RNA-seq |
Experimental & molecular medicine |
Medium |
37121967
|
| 2017 |
Emerin is required for Mkl1 nuclear accumulation and maximal SRF-Mkl1-dependent gene expression in a substrate stiffness-dependent manner in fibroblasts. Emerin is dispensable on more compliant substrates. A constitutively active Mkl1 bypasses the requirement for Emerin. |
Emerin knockout fibroblasts, nuclear localization assay for Mkl1, luciferase reporter, polyacrylamide gel substrates of defined stiffness, constitutively active Mkl1 rescue |
Journal of cell science |
Medium |
28576971
|
| 2014 |
S1P-induced RhoA activation leads to nuclear accumulation of MRTF-A in cardiomyocytes. Pharmacological inhibition or siRNA knockdown of MRTF-A significantly diminishes S1P-mediated CCN1 expression, and S1P-induced cardioprotection against simulated ischemia/reperfusion is significantly reduced by MRTF-A inhibition. |
Nuclear accumulation assay, MRTF-A knockdown/pharmacological inhibition, CCN1 expression assay, simulated I/R apoptosis assay, RhoA manipulation |
Journal of molecular and cellular cardiology |
Medium |
25106095
|
| 2019 |
MKL1 interacts with AP-1 and SMAD3 to trans-activate CTGF in hepatocytes in response to high glucose treatment, contributing to hepatic stellate cell activation in a non-cell-autonomous manner. Genetic ablation or pharmacological inhibition of MKL1 in hepatocytes abrogates the pro-fibrogenic effect. |
ChIP (MKL1 binding to CTGF promoter), Co-IP (MKL1-AP-1-SMAD3), conditioned medium experiments, siRNA knockdown, MKL1 KO mice |
Biochimica et biophysica acta. Gene regulatory mechanisms |
Medium |
30951901
|