Publications by authors named "Mafei Xu"

11 Publications

  • Page 1 of 1

Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson's disease through mitochondrial dysfunction.

PLoS Genet 2020 06 24;16(6):e1008868. Epub 2020 Jun 24.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340320PMC
June 2020

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment.

Sci Adv 2020 May 29;6(18):eaaz8031. Epub 2020 Apr 29.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII's oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aaz8031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190335PMC
May 2020

Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1.

J Clin Invest 2020 04;130(4):1782-1792

Department of Molecular and Cellular Biology, and.

Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein-independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI126327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108891PMC
April 2020

Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway.

Sci Adv 2019 10 9;5(10):eaax6366. Epub 2019 Oct 9.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aax6366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785246PMC
October 2019

Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development.

Sci Rep 2017 06 9;7(1):3136. Epub 2017 Jun 9.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been shown to inhibit myogenesis and skeletal muscle metabolism in vitro. However, its precise role and in vivo function in muscle development has yet to be clearly defined. COUP-TFII protein expression level is high in undifferentiated progenitors and gradually declines during differentiation, raising an important question of whether downregulation of COUP-TFII expression is required for proper muscle cell differentiation. In this study, we generated a mouse model ectopically expressing COUP-TFII in myogenic precursors to maintain COUP-TFII activity during myogenesis and found that elevated COUP-TFII activity resulted in inefficient skeletal muscle development. Using in vitro cell culture and in vivo mouse models, we showed that COUP-TFII hinders myogenic development by repressing myoblast fusion. Mechanistically, the inefficient muscle cell fusion correlates well with the transcriptional repression of Npnt, Itgb1D and Cav3, genes important for cell-cell fusion. We further demonstrated that COUP-TFII also reduces the activation of focal adhesion kinase (FAK), an integrin downstream regulator which is essential for fusion process. Collectively, our studies highlight the importance of down-regulation of COUP-TFII signaling to allow for the induction of factors crucial for myoblast fusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-03475-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466650PMC
June 2017

MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer.

Oncotarget 2016 Mar;7(12):14673-83

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as a critical regulator of glycolysis in prostate cancer cells, which in turn controls cancer cell growth, invasion, and the tumorigenic capability. More importantly, we identified that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a steroid receptor superfamily member, transcriptionally regulates the expression of MPC1. We further demonstrate that COUP-TFII, which is upregulated in the prostate cancer patient, regulates MPC1 and glycolysis to promote tumor growth and metastasis. Our findings reveal that COUP-TFII represses MPC1 expression in prostate cancer cells to facilitate a metabolism switch to increase glycolysis and promote cancer progression. This observation raises an intriguing possibility of targeting COUP-TFII to modulate cancer cell metabolism for prostate cancer intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.7405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924743PMC
March 2016

The role of the orphan nuclear receptor COUP-TFII in tumorigenesis.

Acta Pharmacol Sin 2015 Jan 6;36(1):32-6. Epub 2014 Oct 6.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

The chicken ovalbumin upstream promoter transcription factors (COUP-TFs), members of the nuclear receptor superfamily, consist of two highly homologous subtypes, COUP-TFI (EAR-3, NR2F1) and COUP-TFII (ARP-1, NR2F2). They are referred to as orphan receptors because the COUP-TF ligands have yet to be identified. Since the discovery of COUP-TFs in 1986, extensive studies have demonstrated their crucial functions in a variety of developmental processes, such as organogenesis, angiogenesis, and metabolic homeostasis. Recently, emerging evidence has highlighted that COUP-TFs, specifically COUP-TFII, play important roles in tumorigenesis. In this review, we will discuss the critical functions of COUP-TFII in the development of the tumor microenvironment, the progression of various cancers, and its underlying mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/aps.2014.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571324PMC
January 2015

NR2F1 mutations cause optic atrophy with intellectual disability.

Am J Hum Genet 2014 Feb 23;94(2):303-9. Epub 2014 Jan 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2014.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928641PMC
February 2014

Microspherule protein 2 associates with ASK1 and acts as a negative regulator of stress-induced ASK1 activation.

FEBS Lett 2012 Jun 15;586(12):1678-86. Epub 2012 May 15.

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

Microspherule protein 2 (MCRS2) has been reported to associate with the cellular function of telomerase inhibition, transcriptional regulation and cellular transformation. Here, we report a novel function of MCRS2 in ASK1 pathway. We found that MCRS2 directly binds to ASK1 in vivo and co-localises with ASK1 in the cytoplasm. Overexpression of MCRS2 inhibited oxidative stress (H(2)O(2))-induced ASK1 activation. Knockdown of MCRS2 expression accelerated p38 and JNK phosphorylation and promoted apoptosis in response to H(2)O(2). Finally, H(2)O(2) treatment induced proteasomal degradation of MCRS2, which was further enhanced by activated ASK1. Our results clearly demonstrate that MCRS2 plays a negative role in stress-induced ASK1 activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.febslet.2012.04.051DOI Listing
June 2012

C-terminal amino acids 290-328 of LPTS/PinX1 confer telomerase inhibition.

Biochem Biophys Res Commun 2010 Aug 8;398(4):683-9. Epub 2010 Jul 8.

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

LPTS/PinX1, a telomerase inhibitor composed of 328 amino acids, binds to the telomere associated protein Pin2/TRF1 and to the telomerase catalytic subunit hTERT. However, the mechanism by which LPTS/PinX1 regulates telomerase activity remains unclear. Here we show, for the first time, that LPTS/PinX1 uses different domains to interact with Pin2/TRF1 and hTERT. The LPTS/PinX1(254-289) fragment specifically binds to Pin2/TRF1, and LPTS/PinX1(290-328) can associate with hTERT. Compared with the full-length LPTS/PinX1 protein, LPTS/PinX1(290-328) shows stronger in vitro telomerase inhibitory activity. Moreover, the LPTS/PinX1 protein was recruited to telomeres for binding to Pin2/TRF1. Overexpression of LPTS/PinX1(290-328), which contains a nucleolus localization signal, in cells resulted in telomere shortening and progressive cell death. Conversely, telomere elongation was induced by expression of the dominant-negative LPTS/PinX1(1-289). Our results suggest that the C-terminal fragment of LPTS/PinX1 (LPTS/PinX1(290-328)) contains a telomerase inhibitory domain that is required for the inhibition of telomere elongation and the induction of cell crisis. Our studies also provide evidence that LPTS/PinX1 interaction with Pin2/TRF1 may play a role in the stabilization of telomeres.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2010.06.136DOI Listing
August 2010

Expression and function on embryonic development of lissencephaly-1 genes in zebrafish.

Acta Biochim Biophys Sin (Shanghai) 2009 Aug;41(8):677-88

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Lissencephaly is a severe disease characterized by brain malformation. The main causative gene of lissencephaly is LIS1. Mutation or deletion of LIS1 leads to proliferation and migration deficiency of neurons in brain development. However, little is known about its biological function in embryonic development. In this article, we identified the expression patterns of zebrafish LIS1 gene and investigated its function in embryonic development. We demonstrated that zebrafish consisted of two LIS1 genes, LIS1a and LIS1b. Bioinformatics analysis revealed that LIS1 genes were conserved in evolution both in protein sequences and genomic structures. The expression patterns of zebrafish LIS1a and LIS1b showed that both transcripts were ubiquitously expressed at all embryonic developmental stages and in adult tissues examined. At the protein level, the LIS1 products mainly exist in brain tissue and in embryos at early stages as shown by western blotting analysis. The whole-mount immunostaining data showed that LIS1 proteins were distributed all over the embryos from 1-cell stage to 5 day post-fertilization. Knockdown of LIS1 protein expression through morpholino antisense oligonucleotides resulted in many developmental deficiencies in zebrafish, including brain malformation, circulation abnormality, and body curl. Taken together, our study suggested that zebrafish LIS1 plays a very important role in embryonic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/abbs/gmp056DOI Listing
August 2009