Forkhead Box F2 Regulation of Platelet-derived Growth Factor and Myocardin/Serum Response Factor Signaling Is Essential for Intestinal Development

Bolte, Craig; Ren, Xiaomeng; Tomley, Tatiana; Ustiyan, Vladimir; Pradhan, Arun; Hoggatt, April M.; Kalin, Tanya V.; Herring, B. Paul; Kalinichenko, Vladimir V.

doi:10.1074/jbc.m114.609487

Cited by 51 publications

(52 citation statements)

References 62 publications

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“…Foxf2 is first expressed in the neural crest and in mice regulates pathways involved in mural cell (pericyte and vascular smooth muscle cell) differentiation, including the pdgfβ and serum response factor pathways. 14,23 We did not see haemorrhage in the zebrafish foxf2 mutant model during embryonic stages. We note that we knocked out only one of two foxf2 genes in zebrafish, and even though mural cell markers have changed expression in foxf2b mutants, there might be genetic compensation from the foxf2a gene that could make the phenotype less severe.…”

Section: Discussionmentioning

confidence: 59%

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Chauhan¹,

Arnold²,

Chu³

et al. 2016

The Lancet Neurology

135

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Summary Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms.

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Section: Discussionmentioning

confidence: 59%

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Chauhan¹,

Arnold²,

Chu³

et al. 2016

The Lancet Neurology

135

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“…Flag-tagged FoxF1 and FoxF2 specifically bound to the p21 Cip1 promoter DNA as shown by ChIP (Figure 7C). Both FoxF1 and FoxF2 also bound to the PDGFb promoter (Figure 7D), a known transcriptional target of the FoxF genes (21, 41). Altogether, these data indicate that FoxF1 and FoxF2 directly inhibit p21 Cip1 transcription in rhabdomyosarcoma cells.…”

Section: Resultsmentioning

confidence: 99%

FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor

et al. 2016

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The role of Forkhead Box F1 (FoxF1) transcription factor in carcinogenesis is not well characterized. Depending on tissue and histological type of cancer, FoxF1 was shown to be either oncogene or tumor suppressor. Alveolar rhabdomyosarcoma (RMS) is the most aggressive pediatric soft tissue sarcoma. While FoxF1 is highly expressed in alveolar RMS, the functional role of FoxF1 in RMS is unknown. The present study demonstrates that expression of FoxF1 and its closely related transcription factor FoxF2 are essential for rhabdomyosarcoma tumor growth. Depletion of FoxF1 or FoxF2 in rhabdomyosarcoma cells decreased tumor growth in orthotopic mouse models of RMS. The decreased tumorigenesis was associated with the reduced tumor cell proliferation. Cell cycle regulatory proteins Cdk2, Cdk4/6, Cyclin D1 and Cyclin E2 were decreased in FoxF1- and FoxF2-deficient RMS tumors. Depletion of either FoxF1 or FoxF2 delayed G1-S cell cycle progression, decreased levels of phosphorylated Rb and increased protein levels of the CDK inhibitors, p21Cip1 and p27Kip1. Depletion of both FoxF1 and FoxF2 in tumor cells completely abrogated RMS tumor growth in mice. Overexpression of either FoxF1 or FoxF2 in tumor cells was sufficient to increase carcinogenesis in orthotopic RMS mouse model. FoxF1 and FoxF2 directly bound to and repressed transcriptional activity of p21Cip1 promoter through −556/−545 bp region, but did not affect p27Kip1 transcription. Knockdown of p21Cip1 restored cell cycle progression in the FoxF1- or FoxF2-deficient tumor cells. Altogether, FoxF1 and FoxF2 promoted RMS tumorigenesis by inducing tumor cell proliferation via transcriptional repression of p21Cip1 gene promoter. Due to robust oncogenic activity in RMS tumors, FoxF1 and FoxF2 may represent promising targets for anti-tumor therapy.

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“…SMCs within the vascular wall exist in predominantly two phenotypes: a contractile phenotype and a synthetic phenotype. Transformation from the quiescent contractile phenotype to the active synthetic phenotype can be stimulated by numerous growth factors, including PDGF-BB [75] . The synthetic SMCs phenotype is actively involved in de novo protein synthesis and as such may experience ERS if the protein-folding machinery of the ER is overwhelmed by the demand of newly synthesized proteins [76] .…”

Section: Endoplasmic Reticulum Stress Regulates Cardiovascular Physiomentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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Forkhead Box F2 Regulation of Platelet-derived Growth Factor and Myocardin/Serum Response Factor Signaling Is Essential for Intestinal Development

Cited by 51 publications

References 62 publications

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

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