IQGAP1 and NWASP promote human cancer cell dissemination and metastasis by regulating ß1-integrin via FAK and MRTF/SRF.

Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that ß1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo. We identify IQGAP1 and neural Wiskott-Aldrich syndrome protein (NWASP) as regulators of ß1-integrin transcription and protein expression in prostate and breast cancer cells. IQGAP1 and NWASP depletion in cancer cells decreases adhesion to ECs in vitro and retention in the lung vasculature and metastatic lung nodule formation in vivo. Mechanistically, NWASP and IQGAP1 act downstream of Cdc42 to increase ß1-integrin expression both via extracellular signal-regulated kinase (ERK)/focal adhesion kinase signaling at the protein level and by myocardin-related transcription factor/serum response factor (SRF) transcriptionally. Our results identify IQGAP1 and NWASP as potential therapeutic targets to reduce early metastatic dissemination.

SRF transcriptionally regulates the oligodendrocyte cytoskeleton during CNS myelination.

Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)-a transcription factor known to regulate expression of actin and actin regulators in other cell types-as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the mechanistic role of SRF in oligodendrocyte lineage cells. Here, we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in oligodendrocyte precursor cells and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Surprisingly, oligodendrocyte-restricted loss of SRF results in upregulation of gene signatures associated with aging and neurodegenerative diseases. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies an essential pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.

Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function.

RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics.

Myocardin regulates fibronectin expression and secretion from human pleural mesothelial cells.

During the progression of pleural fibrosis, pleural mesothelial cells (PMCs) undergo a phenotype switching process known as mesothelial-mesenchymal transition (MesoMT). During MesoMT, transformed PMCs become myofibroblasts that produce increased extracellular matrix (ECM) proteins, including collagen and fibronectin (FN1) that is critical to develop fibrosis. Here, we studied the mechanism that regulates FN1 expression in myofibroblasts derived from human pleural mesothelial cells (HPMCs). We found that myocardin (Myocd), a transcriptional coactivator of serum response factor (SRF) and a master regulator of smooth muscle and cardiac muscle differentiation, strongly controls FN1 gene expression. Myocd gene silencing markedly inhibited FN1 expression. FN1 promoter analysis revealed that deletion of the Smad3-binding element diminished FN1 promoter activity, whereas deletion of the putative SRF-binding element increased FN1 promoter activity. Smad3 gene silencing decreased FN1 expression, whereas SRF gene silencing increased FN1 expression. Moreover, SRF competes with Smad3 for binding to Myocd. These results indicate that Myocd activates FN1 expression through Smad3, whereas SRF inhibits FN1 expression in HPMCs. In HPMCs, TGF-ß induced Smad3 nuclear localization, and the proximity ligation signal between Myocd and Smad3 was markedly increased after TGF-ß stimulation at nucleus, suggesting that TGF-ß facilitates nuclear translocation of Smad3 and interaction between Smad3 and Myocd. Moreover, Myocd and Smad3 were coimmunoprecipitated and isolated Myocd and Smad3 proteins directly bound each other. Chromatin immunoprecipitation assays revealed that Myocd interacts with the FN1 promoter at the Smad3-binding consensus sequence. The results indicate that Myocd regulates FN1 gene activation through interaction and activation of the Smad3 transcription factor.NEW & NOTEWORTHY During phenotype switching from mesothelial to mesenchymal, pleural mesothelial cells (PMCs) produce extracellular matrix (ECM) proteins, including collagen and fibronectin (FN1), critical components in the development of fibrosis. Here, we found that myocardin, a transcriptional coactivator of serum response factor (SRF), strongly activates FN1 expression through Smad3, whereas SRF inhibits FN1 expression. This study provides insights about the regulation of FN1 that could lead to the development of novel interventional approaches to prevent pleural fibrosis.

Serum response factor promoting axonal regeneration by activating the Ras-Raf-Cofilin signaling pathway after the spinal cord injury.

INTRODUCTION: Serum response factor (SRF) is important in muscle development, tissue repair, and neuronal regulation. OBJECTIVES: This research aims to thoroughly examine the effects of SRF on spinal cord injury (SCI) and its ability to significantly impact the recovery and regeneration of neuronal axons. METHODS: The researchers created rat models of SCI and scratch injury to primary spinal cord neurons to observe the expression of relevant factors after neuronal injury. RESULTS: We found that the SRF, Ras, Raf, and cofilin levels increased after injury and gradually returned to normal levels. Afterward, researchers gave rats with SCI an SRF inhibitor (CCG1423) and studied the effects with nuclear magnetic resonance and transmission electron microscopy. The SRF inhibitor rodents had worse spinal cord recovery and axon regrowth than the control group. And the apoptosis of primary neurons after scratch injury was significantly higher in the SRF inhibitor group. Additionally, the researchers utilized lentiviral transfection to modify the SRF expression in neurons. SRF overexpression increased neuron migration while silencing SRF decreased it. Finally, Western blotting and RT-PCR were conducted to examine the expression changes of related factors upon altering SRF expression. The results revealed SRF overexpression increased Ras, Raf, and cofilin expression. Silencing SRF decreased Ras, Raf, and Cofilin expression. CONCLUSION: Based on our research, the SRF promotes axonal regeneration by activating the "Ras-Raf-Cofilin" signaling pathway.

SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration.

Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These SrfGFAP-ERCKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains of Srf knockout mice exhibited neuroprotection against kainic-acid induced excitotoxic cell death. Relevant to human neurodegenerative diseases, SrfGFAP-ERCKO astrocytes abrogate nigral dopaminergic neuron death and reduce ß-amyloid plaques in mouse models of Parkinson's and Alzheimer's disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.

Vascular injury activates the ELK1/SND1/SRF pathway to promote vascular smooth muscle cell proliferative phenotype and neointimal hyperplasia.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation is the leading cause of vascular stenosis or restenosis. Therefore, investigating the molecular mechanisms and pivotal regulators of the proliferative VSMC phenotype is imperative for precisely preventing neointimal hyperplasia in vascular disease. METHODS: Wire-induced vascular injury and aortic culture models were used to detect the expression of staphylococcal nuclease domain-containing protein 1 (SND1). SMC-specific Snd1 knockout mice were used to assess the potential roles of SND1 after vascular injury. Primary VSMCs were cultured to evaluate SND1 function on VSMC phenotype switching, as well as to investigate the mechanism by which SND1 regulates the VSMC proliferative phenotype. RESULTS: Phenotype-switched proliferative VSMCs exhibited higher SND1 protein expression compared to the differentiated VSMCs. This result was replicated in primary VSMCs treated with platelet-derived growth factor (PDGF). In the injury model, specific knockout of Snd1 in mouse VSMCs reduced neointimal hyperplasia. We then revealed that ETS transcription factor ELK1 (ELK1) exhibited upregulation and activation in proliferative VSMCs, and acted as a novel transcription factor to induce the gene transcriptional activation of Snd1. Subsequently, the upregulated SND1 is associated with serum response factor (SRF) by competing with myocardin (MYOCD). As a co-activator of SRF, SND1 recruited the lysine acetyltransferase 2B (KAT2B) to the promoter regions leading to the histone acetylation, consequently promoted SRF to recognize the specific CArG motif, and enhanced the proliferation- and migration-related gene transcriptional activation. CONCLUSIONS: The present study identifies ELK1/SND1/SRF as a novel pathway in promoting the proliferative VSMC phenotype and neointimal hyperplasia in vascular injury, predisposing the vessels to pathological remodeling. This provides a potential therapeutic target for vascular stenosis.

MKL/SRF and Bcl6 mutual transcriptional repression safeguards the fate and positioning of neocortical progenitor cells mediated by RhoA.

During embryogenesis, multiple intricate and intertwined cellular signaling pathways coordinate cell behavior. Their slightest alterations can have dramatic consequences for the cells and the organs they form. The transcriptional repressor Bcl6 was recently found as important for brain development. However, its regulation and integration with other signals is unknown. Using in vivo functional approaches combined with molecular mechanistic analysis, we identified a reciprocal regulatory loop between B cell lymphoma 6 (Bcl6) and the RhoA-regulated transcriptional complex megakaryoblastic leukemia/serum response factor (MKL/SRF). We show that Bcl6 physically interacts with MKL/SRF, resulting in a down-regulation of the transcriptional activity of both Bcl6 and MKL/SRF. This molecular cross-talk is essential for the control of proliferation, neurogenesis, and spatial positioning of neural progenitors. Overall, our data highlight a regulatory mechanism that controls neuronal production and neocortical development and reveal an MKL/SRF and Bcl6 interaction that may have broader implications in other physiological functions and in diseases.

Sall1 and Sall4 cooperatively interact with Myocd and SRF to promote cardiomyocyte proliferation by regulating CDK and cyclin genes.

Sall1 and Sall4 (Sall1/4), zinc-finger transcription factors, are expressed in the progenitors of the second heart field (SHF) and in cardiomyocytes during the early stages of mouse development. To understand the function of Sall1/4 in heart development, we generated heart-specific Sall1/4 functionally inhibited mice by forced expression of the truncated form of Sall4 (ΔSall4) in the heart. The ΔSall4-overexpression mice exhibited a hypoplastic right ventricle and outflow tract, both of which were derived from the SHF, and a thinner ventricular wall. We found that the numbers of proliferative SHF progenitors and cardiomyocytes were reduced in ΔSall4-overexpression mice. RNA-sequencing data showed that Sall1/4 act upstream of the cyclin-dependent kinase (CDK) and cyclin genes, and of key transcription factor genes for the development of compact cardiomyocytes, including myocardin (Myocd) and serum response factor (Srf). In addition, ChIP-sequencing and co-immunoprecipitation analyses revealed that Sall4 and Myocd form a transcriptional complex with SRF, and directly bind to the upstream regulatory regions of the CDK and cyclin genes (Cdk1 and Ccnb1). These results suggest that Sall1/4 are critical for the proliferation of cardiac cells via regulation of CDK and cyclin genes that interact with Myocd and SRF.

MRTF-A gain-of-function in mice impairs homeostatic renewal of the intestinal epithelium.

The actin-regulated transcription factor MRTF-A represents a central relay in mechanotransduction and controls a subset of SRF-dependent target genes. However, gain-of-function studies in vivo are lacking. Here we characterize a conditional MRTF-A transgenic mouse model. While MRTF-A gain-of-function impaired embryonic development, induced expression of constitutively active MRTF-A provoked rapid hepatocyte ballooning and liver failure in adult mice. Specific expression in the intestinal epithelium caused an erosive architectural distortion, villus blunting, cryptal hyperplasia and colonic inflammation, resulting in transient weight loss. Organoids from transgenic mice repeatedly induced in vitro showed impaired self-renewal and defective cryptal compartments. Mechanistically, MRTF-A gain-of-function decreased proliferation and increased apoptosis, but did not induce fibrosis. MRTF-A targets including Acta2 and Pai-1 were induced, whereas markers of stem cells and differentiated cells were reduced. Our results suggest that activated MRTF-A in the intestinal epithelium shifts the balance between proliferation, differentiation and apoptosis.

Mural Serum Response Factor (SRF) Deficiency Provides Insights into Retinal Vascular Functionality and Development.

Serum response factor (SRF) controls the expression of muscle contraction and motility genes in mural cells (MCs) of the vasculature. In the retina, MC-SRF is important for correct angiogenesis during development and the continuing maintenance of the vascular tone. The purpose of this study was to provide further insights into the effects of MC SRF deficiency on the vasculature and function of the mature retina in SrfiMCKO mice that carry a MC-specific deletion of Srf. Retinal morphology and vascular integrity were analyzed in vivo via scanning laser ophthalmoscopy (SLO), angiography, and optical coherence tomography (OCT). Retinal function was evaluated with full-field electroretinography (ERG). We found that retinal blood vessels of these mutants exhibited different degrees of morphological and functional alterations. With increasing severity, we found vascular bulging, the formation of arteriovenous (AV) anastomoses, and ultimately, a retinal detachment (RD). The associated irregular retinal blood pressure and flow distribution eventually induced hypoxia, indicated by a negative ERG waveform shape. Further, the high frequency of interocular differences in the phenotype of individual SrfiMCKO mice points to a secondary nature of these developments far downstream of the genetic defect and rather dependent on the local retinal context.

Ac-SDKP promotes KIF3A-mediated ß-catenin suppression through a ciliary mechanism to constrain silica-induced epithelial-myofibroblast transition.

Kinesin family member 3 A (KIF3A) decrease have been reported in silicotic patients and rats. However, the detailed mechanisms of KIF3A in silicosis remain unknown. In this study, we demonstrated that KIF3A effectively blocked the expression of ß-catenin and downstream myocardin-related transcription factor (MRTF)-A/serum response factor (SRF) signaling, thus inhibiting silica-induced epithelial-myofibroblast transition (EMyT). Moreover, KIF3A was identified as a downstream mediator of an antifibrotic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Knockdown of KIF3A expression reactivated ß-catenin/myocardin-related transcription factor (MRTF)-A/serum response factor (SRF) signaling that was attenuated by Ac-SDKP in vitro. Collectively, our findings suggest that Ac-SDKP plays its anti-fibrosis role via KIF3A-mediated ß-catenin suppression, at least in part, in both in vivo model of silicosis and in vitro model of EMyT.

Endogenous SOLOIST/MRTFB i4, a Neuronal Isoform of MKL2/MRTFB, Positively and Negatively Regulates SRF Target Immediate Early Genes in Neuro-2a Cells.

Megakaryoblastic leukemia 2 (MKL2)/myocardin-related transcription factor-B (MRTFB) is a serum response factor (SRF) cofactor that is enriched in the brain and controls SRF target genes and neuronal morphology. There are at least four isoforms of MKL2/MRTFB. Among these, MKL2/MRTFB isoform 1 and spliced neuronal long isoform of SRF transcriptional coactivator (SOLOIST)/MRTFB isoform 4 (MRTFB i4) are highly expressed in neurons. Although, when overexpressed in neurons, isoform 1 and SOLOIST/MRTFB i4 have opposing effects on dendritic morphology and differentially regulate SRF target genes, it is unknown how endogenous SOLOIST/MRTFB i4 regulates gene expression. Using isoform-specific knockdown, we investigated the role of endogenous SOLOST/MRTFB i4 in regulating the expression of other MKL2/MRTFB isoforms and SRF-target genes in Neuro-2a cells. Knockdown of SOLOIST/MRTFB i4 downregulated SOLOIST/MRTFB i4, while it upregulated isoform 1 without affecting isoform 3. Knockdown of SOLOIST/MRTFB i4 downregulated the SRF target immediate early genes egr1 and Arc, while it upregulated c-fos. Double knockdown of isoform 1 and SOLOIST/MRTFB i4 inhibited c-fos expression. Taken together, our findings in Neuro-2a cells suggest that endogenous SOLOIST/MRTFB i4 positively regulates egr1 and Arc expression. In addition, endogenous SOLOIST/MRTFB i4 may negatively regulate c-fos expression, possibly by downregulating isoform 1 in Neuro-2a cells.

Serum Response Factor Reduces Gene Expression Noise and Confers Cell State Stability.

The role of serum response factor (Srf), a central mediator of actin dynamics and mechanical signaling, in cell identity regulation is debated to be either a stabilizer or a destabilizer. We investigated the role of Srf in cell fate stability using mouse pluripotent stem cells. Despite the fact that serum-containing cultures yield heterogeneous gene expression, deletion of Srf in mouse pluripotent stem cells leads to further exacerbated cell state heterogeneity. The exaggerated heterogeneity is detectible not only as increased lineage priming but also as the developmentally earlier 2C-like cell state. Thus, pluripotent cells explore more variety of cellular states in both directions of development surrounding naïve pluripotency, a behavior that is constrained by Srf. These results support that Srf functions as a cell state stabilizer, providing rationale for its functional modulation in cell fate intervention and engineering.

SRF inhibitors reduce prostate cancer cell proliferation through cell cycle arrest in an isogenic model of castrate-resistant prostate cancer.

Castrate-resistant prostate cancer (CRPC) is challenging to treat, despite improvements with next-generation anti-androgens such as enzalutamide, due to acquired resistance. One of the mechanisms of such resistance includes aberrant activation of co-factors of the androgen receptor (AR), such as the serum response factor (SRF), which was associated with prostate cancer progression and resistance to enzalutamide. Here, we show that inhibition of SRF with three small molecules (CCG-1423, CCG-257081 and lestaurtinib), singly and in combination with enzalutamide, reduces cell viability in an isogenic model of CRPC. The effects of these inhibitors on the cell cycle, singly and in combination with enzalutamide, were assessed with western blotting, flow cytometry and ß-galactosidase staining. In the androgen deprivation-sensitive LNCaP parental cell line, a synergistic effect between enzalutamide and all three inhibitors was demonstrated, while the androgen deprivation-resistant LNCaP Abl cells showed synergy only with the lestaurtinib and enzalutamide combination, suggesting a different mechanism of action of the CCG series of compounds in the absence and presence of androgens. Through analysis of cell cycle checkpoint proteins, flow cytometry and ß-galactosidase staining, we showed that all three SRF inhibitors, singly and in combination with enzalutamide, induced cell cycle arrest and decreased S phase. While CCG-1423 had a more pronounced effect on the expression of cell cycle checkpoint proteins, CCG-257081 and lestaurtinib decreased proliferation also through induction of cellular senescence. In conclusion, we show that inhibition of an AR co-factors, namely SRF, provides a promising approach to overcoming resistance to AR inhibitors currently used in the clinic.

SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis.

Changes in neuronal activity modulate the vulnerability of motoneurons (MNs) in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). So far, the molecular basis of neuronal activity's impact in ALS is poorly understood. Herein, we investigated the impact of deleting the neuronal activity-stimulated transcription factor (TF) serum response factor (SRF) in MNs of SOD1G93A mice. SRF was present in vulnerable MMP9+ MNs. Ablation of SRF in MNs induced an earlier disease onset starting around 7-8 weeks after birth, as revealed by enhanced weight loss and decreased motor ability. This earlier disease onset in SRF-depleted MNs was accompanied by a mild elevation of neuroinflammation and neuromuscular synapse degeneration, whereas overall MN numbers and mortality were unaffected. In SRF-deficient mice, MNs showed impaired induction of autophagy-encoding genes, suggesting a potentially new SRF function in transcriptional regulation of autophagy. Complementary, constitutively active SRF-VP16 enhanced autophagy-encoding gene transcription and autophagy progression in cells. Furthermore, SRF-VP16 decreased ALS-associated aggregate induction. Chemogenetic modulation of neuronal activity uncovered SRF as having important TF-mediating activity-dependent effects, which might be beneficial to reduce ALS disease burden. Thus, our data identify SRF as a gene regulator connecting neuronal activity with the cellular autophagy program initiated in degenerating MNs.

Serum response factor activates peroxidasin transcription to block senescence of hepatic stellate cells.

AIMS: Aberrant liver fibrosis is a hallmark event in end-stage liver diseases. Hepatic stellate cells (HSCs) are considered the major source of myofibroblasts in the liver that produce extracellular matrix proteins to promote liver fibrosis. HSCs undergo senescence in response to various stimuli, a process that can be exploited to dampen liver fibrosis. We investigated the role of serum response factor (SRF) in this process. METHODS AND MATERIALS: Senescence was induced HSCs by serum withdrawal or progressive passage. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP). RESULTS: SRF expression was down-regulated in HSCs entering into senescence. Coincidently, SRF depletion by RNAi accelerated HSC senescence. Of note, treatment of an anti-oxidant (N-acetylcysteine or NAC) blocked HSC senescence by SRF deficiency suggesting that SRF may antagonize HSC senescence by eliminating excessive reactive oxygen species (ROS). PCR-array based screening identified peroxidasin (PXDN) as a potential target for SRF in HSCs. PXDN expression was inversely correlated with HSC senescence whereas PXDN knockdown accelerated HSC senescence. Further analysis reveals that SRF directly bound to the PXDN promoter and activated PXDN transcription. Consistently, PXDN over-expression protected whereas PXDN depletion amplified HSC senescence. Finally, PXDN knockout mice displayed diminished liver fibrosis compared to wild type mice when subjected to bile duct ligation (BDL). SIGNIFICANCE: Our data suggest that SRF, via its downstream target PXDN, plays a key role in regulating HSC senescence.

Quercetin induces dual specificity phosphatase 5 via serum response factor.

The phytochemical quercetin has gained attention for its antiinflammatory and anti-tumorigenic properties in various types of cancer. Tumorigenesis involves the aberrant regulation of kinase/phosphatase, highlighting the importance of maintaining homeostasis. Dual Specificity Phosphatase (DUSP) plays a crucial role in controlling the phosphorylation of ERK. The current study aimed to clone the DUSP5 promoter, and investigate its transcriptional activity in the presence of quercetin. The results revealed that quercetin-induced DUSP5 expression is associated with the serum response factor (SRF) binding site located in the DUSP5 promoter. The deletion of this site abolished the luciferase activity induced by quercetin, indicating its vital role in quercetin-induced DUSP5 expression. SRF protein is a transcription factor that potentially contributes to quercetin-induced DUSP5 expression at the transcriptional level. Additionally, quercetin enhanced SRF binding activity without changing its expression. These findings provide evidence of how quercetin affects anti-cancer activity in colorectal tumorigenesis by inducing SRF transcription factor activity, thereby increasing DUSP5 expression at the transcriptional level. This study highlights the importance of investigating the molecular mechanisms underlying the anti-cancer properties of quercetin, and suggests its potential use in cancer therapy. [BMB Reports 2023; 56(9): 508-513].

Plasticity in airway smooth muscle differentiation during mouse lung development.

It has been proposed that smooth muscle differentiation may physically sculpt airway epithelial branches in mammalian lungs. Serum response factor (SRF) acts with its co-factor myocardin to activate the expression of contractile smooth muscle markers. In the adult, however, smooth muscle exhibits a variety of phenotypes beyond contractile, and these are independent of SRF/myocardin-induced transcription. To determine whether a similar phenotypic plasticity is exhibited during development, we deleted Srf from the mouse embryonic pulmonary mesenchyme. Srf-mutant lungs branch normally, and the mesenchyme displays mechanical properties indistinguishable from controls. scRNA-seq identified an Srf-null smooth muscle cluster, wrapping the airways of mutant lungs, which lacks contractile smooth muscle markers but retains many features of control smooth muscle. Srf-null embryonic airway smooth muscle exhibits a synthetic phenotype, compared with the contractile phenotype of mature wild-type airway smooth muscle. Our findings identify plasticity in embryonic airway smooth muscle and demonstrate that a synthetic smooth muscle layer promotes airway branching morphogenesis.

Myocardin-related transcription factor A, regulated by serum response factor, contributes to diabetic cardiomyopathy in mice.

AIMS: Diabetic cardiomyopathy is a significant contributor to the global pandemic of heart failure. In the present study we investigated the involvement of myocardin-related transcription factor A (MRTF-A), a transcriptional regulator, in this process. MATERIALS AND METHODS: Diabetic cardiomyopathy was induced in mice by feeding with a high-fat diet (HFD) or streptozotocin (STZ) injection. KEY FINDINGS: We report that MRTF-A was up-regulated in the hearts of mice with diabetic cardiomyopathy. MRTF-A expression was also up-regulated by treatment with palmitate in cultured cardiomyocytes in vitro. Mechanistically, serum response factor (SRF) bound to the MRTF-A gene promoter and activated MRTF-A transcription in response to pro-diabetic stimuli. Knockdown of SRF abrogated MRTF-A induction in cardiomyocytes treated with palmitate. When cardiomyocytes conditional MRTF-A knockout mice (MRTF-A CKO) and wild type (WT) mice were placed on an HFD to induce diabetic cardiomyopathy, it was found that the CKO mice and the WT mice displayed comparable metabolic parameters including body weight, blood insulin concentration, blood cholesterol concentration, and glucose tolerance. However, both systolic and diastolic cardiac function were exacerbated by MRTF-A deletion in the heart. SIGNIFICANCE: These data suggest that MRTF-A up-regulation might serve as an important compensatory mechanism to safeguard the deterioration of cardiac function during diabetic cardiomyopathy.