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Maria Jose Martinez - One of the best experts on this subject based on the ideXlab platform.
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Molecular and cellular insights into the role of SND1 in lipid metabolism.
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2020Co-Authors: Hiart Navarro-imaz, Yolanda Chico, Olatz Fresnedo, Begona Ochoa, Maria Jose Martinez, Itsaso Garcia-arcos, Yuri RuedaAbstract:Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an evolutionarily conserved protein present in eukaryotic cells from protozoa to mammals. SND1 has gained importance because it is overexpressed in aggressive cancer cells and diverse primary tumors. Indeed, it is regarded as a marker of cancer malignity. A broad range of molecular functions and the participation in many cellular processes have been attributed to SND1, mostly related to the regulation of gene expression. An increasing body of evidence points to a relevant relationship between SND1 and lipid metabolism. In this review, we summarize the knowledge about SND1 and its molecular and functional relationship with lipid metabolism. We highlight that SND1 plays a direct role in the regulation of cholesterol metabolism by affecting the activation of sterol response element-binding protein 2 (SREBP2) and we propose that that might have implications in the response of lipid homeostasis to stress situations.
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Insights Into SND1 Oncogene Promoter Regulation.
Frontiers in oncology, 2018Co-Authors: Begona Ochoa, Yolanda Chico, Maria Jose MartinezAbstract:The staphylococcal nuclease and Tudor domain containing 1 gene (SND1), also known as Tudor-SN, TSN or p100, encodes an evolutionarily conserved protein with invariant domain composition. SND1 contains four repeated staphylococcal nuclease domains and a single Tudor domain, which confer it endonuclease activity and extraordinary capacity for interacting with nucleic acids, individual proteins and protein complexes. Originally described as a transcriptional coactivator, SND1 plays fundamental roles in the regulation of gene expression, including RNA splicing, interference, stability, and editing, as well as in the regulation of protein and lipid homeostasis. Recently, SND1 has gained attention as a potential disease biomarker due to its positive correlation with cancer progression and metastatic spread. Such functional diversity of SND1 marks this gene as interesting for further analysis in relation with the multiple levels of regulation of SND1 protein production. In this review, we summarize the SND1 genomic region and promoter architecture, the set of transcription factors that can bind the proximal promoter, and the evidence supporting transactivation of SND1 promoter by a number of signal transduction pathways operating in different cell types and conditions. Unraveling the mechanisms responsible for SND1 promoter regulation is of utmost interest to decipher the SND1 contribution in the realm of both normal and abnormal physiology.
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srebp 2 driven transcriptional activation of human SND1 oncogene
Oncotarget, 2017Co-Authors: Sandra Armengol, Yolanda Chico, Enara Arretxe, Leire Enzunza, Irati Llorente, Unai Mendibil, Hiart Navarroimaz, Begona Ochoa, Maria Jose MartinezAbstract:Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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SREBP-2-driven transcriptional activation of human SND1 oncogene.
Oncotarget, 2017Co-Authors: Sandra Armengol, Hiart Navarro-imaz, Yolanda Chico, Enara Arretxe, Leire Enzunza, Irati Llorente, Unai Mendibil, Begona Ochoa, Maria Jose MartinezAbstract:// Sandra Armengol 1 , Enara Arretxe 1 , Leire Enzunza 1 , Irati Llorente 1 , Unai Mendibil 1 , Hiart Navarro-Imaz 1 , Begona Ochoa 1 , Yolanda Chico 1 and Maria Jose Martinez 1 1 Lipids & Liver Research Group, Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Vizcaya, Spain Correspondence to: Maria Jose Martinez, email: mariajose.martinez@ehu.eus Keywords: SND1; Tudor-SN; gene promoter regulation; SREBP-2; SREBP-1 Received: January 04, 2017 Accepted: September 22, 2017 Published: November 21, 2017 ABSTRACT Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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profiling of promoter occupancy by the SND1 transcriptional coactivator identifies downstream glycerolipid metabolic genes involved in tnfα response in human hepatoma cells
Nucleic Acids Research, 2015Co-Authors: Enara Arretxe, Yolanda Chico, Sandra Armengol, Begona Ochoa, Sarai Mula, Maria Jose MartinezAbstract:The NF-κB-inducible Staphylococcal nuclease and tudor domain-containing 1 gene (SND1) encodes a coactivator involved in inflammatory responses and tumorigenesis. While SND1 is known to interact with certain transcription factors and activate client gene expression, no comprehensive mapping of SND1 target genes has been reported. Here, we have approached this question by performing ChIP-chip assays on human hepatoma HepG2 cells and analyzing SND1 binding modulation by proinflammatory TNFα. We show that SND1 binds 645 gene promoters in control cells and 281 additional genes in TNFα-treated cells. Transcription factor binding site analysis of bound probes identified motifs for established partners and for novel transcription factors including HSF, ATF, STAT3, MEIS1/AHOXA9, E2F and p300/CREB. Major target genes were involved in gene expression and RNA metabolism regulation, as well as development and cellular metabolism. We confirmed SND1 binding to 21 previously unrecognized genes, including a set of glycerolipid genes. Knocking-down experiments revealed that SND1 deficiency compromises the glycerolipid gene reprogramming and lipid phenotypic responses to TNFα. Overall, our findings uncover an unexpected large set of potential SND1 target genes and partners and reveal SND1 to be a determinant downstream effector of TNFα that contributes to support glycerophospholipid homeostasis in human hepatocellular carcinoma during inflammation.
Devanand Sarkar - One of the best experts on this subject based on the ideXlab platform.
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Posttranscriptional Inhibition of Protein Tyrosine Phosphatase Nonreceptor Type 23 by Staphylococcal Nuclease and Tudor Domain Containing 1: Implications for Hepatocellular Carcinoma
Hepatology communications, 2019Co-Authors: Nidhi Jariwala, Paul B. Fisher, Rachel G. Mendoza, Mark A. Subler, Jolene J. Windle, Dawn Garcia, Zhao Lai, Nitai D. Mukhopadhyay, Yidong Chen, Devanand SarkarAbstract:Oncoprotein staphylococcal nuclease and tudor domain containing 1 (SND1) regulates gene expression at a posttranscriptional level in multiple cancers, including hepatocellular carcinoma (HCC). Staphylococcal nuclease (SN) domains of SND1 function as a ribonuclease (RNase), and the tudor domain facilitates protein-oligonucleotide interaction. In the present study, we aimed to identify RNA interactome of SND1 to obtain enhanced insights into gene regulation by SND1. RNA interactome was identified by immunoprecipitation (IP) of RNA using anti-SND1 antibody from human HCC cells followed by RNA immunoprecipitation sequencing (RIP-Seq). Among RNA species that showed more than 10-fold enrichment over the control, we focused on the tumor suppressor protein tyrosine phosphatase nonreceptor type 23 (PTPN23) because its regulation by SND1 and its role in HCC are not known. PTPN23 levels were down-regulated in human HCC cells versus normal hepatocytes and in human HCC tissues versus normal adjacent liver, as revealed by immunohistochemistry. In human HCC cells, knocking down SND1 increased and overexpression of SND1 decreased PTPN23 protein. RNA binding and degradation assays revealed that SND1 binds to and degrades the 3'-untranslated region (UTR) of PTPN23 messenger RNA (mRNA). Tetracycline-inducible PTPN23 overexpression in human HCC cells resulted in significant inhibition in proliferation, migration, and invasion and in vivo tumorigenesis. PTPN23 induction caused inhibition in activation of tyrosine-protein kinase Met (c-Met), epidermal growth factor receptor (EGFR), Src, and focal adhesion kinase (FAK), suggesting that, as a putative phosphatase, PTPN23 inhibits activation of these oncogenic kinases. Conclusion: PTPN23 is a novel target of SND1, and our findings identify PTPN23 as a unique tumor suppressor for HCC. PTPN23 might function as a homeostatic regulator of multiple kinases, restraining their activation.
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The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma.
Hepatoma research, 2018Co-Authors: Saranya Chidambaranathan-reghupaty, Paul B. Fisher, Rachel G. Mendoza, Devanand SarkarAbstract:Staphylococcal nuclease and tudor domain containing 1 (SND1) is a protein that regulates a complex array of functions. It controls gene expression through transcriptional activation, mRNA degradation, mRNA stabilization, ubiquitination and alternative splicing. More than two decades of research has accumulated evidence of the role of SND1 as an oncogene in various cancers. It is a promoter of cancer hallmarks like proliferation, invasion, migration, angiogenesis and metastasis. In addition to these functions, it has a role in lipid metabolism, inflammation and stress response. The participation of SND1 in such varied functions makes it distinct from most oncogenes that are relatively more focused in their role. This becomes important in the case of hepatocellular carcinoma (HCC) since in addition to typical cancer drivers, factors like lipid metabolism deregulation and chronic inflammation can predispose hepatocytes to HCC. The objective of this review is to provide a summary of the current knowledge available on SND1, specifically in relation to HCC and to shed light on its prospect as a therapeutic target.
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Abstract 3823: Staphylococcal nuclease and tudor domain containing 1 (SND1) in development and progression of hepatocellular carcinoma
Experimental and Molecular Therapeutics, 2016Co-Authors: Nidhi Jariwala, Rachel Gredler, Paul B. Fisher, Chadia L. Robertson, Maaged A. Akiel, Devaraja Rajasekaran, Arun J. Sanyal, Devanand SarkarAbstract:Staphylococcal nuclease and tudor domain containing 1 (SND1) is identified as an oncogene in hepatocellular carcinoma (HCC) and overexpression of SND1 has been correlated with HCC progression. Here, we present effect of liver specific overexpression of human SND1 in a novel transgenic mouse model. We observe greater tumor load and tumor volume in transgenic mice than wildtype mice, when subjected to chemical carcinogenesis. Approximately 30% of transgenic animals manifest spontaneous tumorigenesis with age. Liver specific expression of cancer stem cell markers such as EpCAM and CD133 as well as inflammatory markers was found to be higher in transgenic mice. SND1 overexpressing hepatocytes show increased activation of insulin and NFκB signaling pathways compared to wildtype hepatocytes. However, no significant differences in liver weight or liver function was noted among transgenic and wildtype animals. Overall, our findings confirm that overexpression of SND1 in vivo plays a vital role in development and progression of HCC. Thus, molecular targeting of SND1 seems to be potential therapeutic intervention for HCC management in patients. Citation Format: Nidhi Jariwala, Devaraja Rajasekaran, Rachel Gredler, Maaged Akiel, Chadia Robertson, Paul Fisher, Arun Sanyal, Devanand Sarkar. Staphylococcal nuclease and tudor domain containing 1 (SND1) in development and progression of hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3823.
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Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) Promotes Hepatocarcinogenesis by Inhibiting Monoglyceride Lipase (MGLL)
The Journal of biological chemistry, 2016Co-Authors: Devaraja Rajasekaran, Paul B. Fisher, Chadia L. Robertson, Maaged A. Akiel, Nidhi Jariwala, Rachel G. Mendoza, Mikhail G. Dozmorov, Devanand SarkarAbstract:Staphylococcal nuclease and tudor domain containing 1 (SND1) is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC), and functions as an oncogene. This study was carried out to identify novel SND1-interacting proteins to better understand its molecular mechanism of action. SND1-interacting proteins were identified by a modified yeast two-hybrid assay. Protein-protein interaction was confirmed by co-immunoprecipitation analysis. Monoglyceride lipase (MGLL) expression was analyzed by quantitative RT-PCR, Western blot, and immunohistochemistry. MGLL-overexpressing clones were analyzed for cell proliferation and cell cycle analysis and in vivo tumorigenesis in nude mice. MGLL was identified as an SND1-interacting protein. Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. MGLL expression was detected in normal human hepatocytes and mouse liver, although it was undetected in human HCC cell lines. An inverse correlation between SND1 and MGLL levels was identified in a human HCC tissue microarray as well as in the TCGA database. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression and a marked decrease in tumor growth in nude mouse xenograft assays. MGLL overexpression inhibited Akt activation that is independent of enzymatic activity of MGLL and overexpression of a constitutively active Akt rescued cells from inhibition of proliferation and restored normal cell cycle progression. This study unravels a novel mechanism of SND1 function and identifies MGLL as a unique tumor suppressor for HCC. MGLL might function as a homeostatic regulator of Akt restraining its activation.
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Role of the staphylococcal nuclease and tudor domain containing 1 in oncogenesis (review).
International journal of oncology, 2014Co-Authors: Nidhi Jariwala, Rachel Gredler, Luni Emdad, Paul B. Fisher, Jyoti Srivastava, Chadia L. Robertson, Maaged A. Akiel, Devaraja Rajasekaran, Devanand SarkarAbstract:The staphylococcal nuclease and tudor domain containing 1 (SND1) is a multifunctional protein overexpressed in breast, prostate, colorectal and hepatocellular carcinomas and malignant glioma. Molecular studies have revealed the multifaceted activities of SND1 involved in regulating gene expression at transcriptional as well as post-transcriptional levels. Early studies identified SND1 as a transcriptional co-activator. SND1 is also a component of RNA-induced silencing complex (RISC) thus mediating RNAi function, a regulator of mRNA splicing, editing and stability, and plays a role in maintenance of cell viability. Such diverse actions allow the SND1 to modulate a complex array of molecular networks, thereby promoting carcinogenesis. Here, we describe the crucial role of SND1 in cancer development and progression, and highlight SND1 as a potential target for therapeutic intervention.
Ruiqin Zhong - One of the best experts on this subject based on the ideXlab platform.
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The Arabidopsis NAC transcription factor NST2 functions together with SND1 and NST1 to regulate secondary wall biosynthesis in fibers of inflorescence stems
Plant signaling & behavior, 2015Co-Authors: Ruiqin ZhongAbstract:Transcriptional regulation of secondary wall biosynthesis in Arabidopsis thaliana has been shown to be mediated by a group of secondary wall NAC master switches, including NST1, NST2, SND1 and VND1 to VND7. It has been shown that VND1 to VND7 regulate secondary wall biosynthesis in vessels, NST1 and NST2 function redundantly in anther endothecium, and SND1 and NST1 are required for secondary wall thickening in fibers of stems. However, it is unknown whether NST2 is involved in regulating secondary wall biosynthesis in fibers of stems. In this report, we demonstrated that similar to SND1, NST2 together with NST1 were highly expressed in interfascicular fibers and xylary fibers but not in vessels of stems. Although simultaneous mutations of SND1 and NST1 have been shown to result in a significant impairment of secondary wall thickening in fibers, a small amount of secondary walls was deposited in fibers during the late stage of stem development. In contrast, simultaneous mutations of SND1, NST1 and NST2 led to a complete loss of secondary wall thickening in fibers. These results demonstrate that NST2 together with SND1 and NST1 regulate secondary wall biosynthesis in fibers of stems.
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Global analysis of direct targets of secondary wall NAC master switches in Arabidopsis.
Molecular plant, 2010Co-Authors: Ruiqin Zhong, Chanhui LeeAbstract:We report the genome-wide analysis of direct target genes of SND1 and VND7, two Arabidopsis thaliana NAC domain transcription factors that are master regulators of secondary wall biosynthesis in fibers and vessels, respectively. Systematic mapping of the SND1 binding sequence using electrophoretic mobility shift assay and transactivation analysis demonstrated that SND1 together with other secondary wall NACs (SWNs), including VND6, VND7, NST1, and NST2, bind to an imperfect palindromic 19-bp consensus sequence designated as secondary wall NAC binding element (SNBE), (T/A)NN(C/T) (T/C/G)TNNNNNNNA(A/C)GN(A/C/T) (A/T), in the promoters of their direct targets. Genome-wide analysis of direct targets of SND1 and VND7 revealed that they directly activate the expression of not only downstream transcription factors, but also a number of non-transcription factor genes involved in secondary wall biosynthesis, cell wall modification, and programmed cell death, the promoters of which all contain multiple SNBE sites. SND1 and VND7 directly regulate the expression of a set of common targets but each of them also preferentially induces a distinct set of direct targets, which is likely attributed to their differential activation strength toward SNBE sites. Complementation study showed that the SWNs were able to rescue the secondary wall defect in the SND1 nst1 mutant, indicating that they are functionally interchangeable. Together, our results provide important insight into the complex transcriptional program and the evolutionary mechanism underlying secondary wall biosynthesis, cell wall modification, and programmed cell death in secondary wall-containing cell types.
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myb83 is a direct target of SND1 and acts redundantly with myb46 in the regulation of secondary cell wall biosynthesis in arabidopsis
Plant and Cell Physiology, 2009Co-Authors: Ryan L Mccarthy, Ruiqin Zhong, Zhenghua YeAbstract:It has been proposed that the transcriptional regulation of secondary wall biosynthesis in Arabidopsis is controlled by a transcriptional network mediated by SND1 and its close homologs. Uncovering all the transcription factors and deciphering their interrelationships in the network are essential for our understanding of the molecular mechanisms underlying the transcriptional regulation of biosynthesis of secondary walls, the major constituent of wood and fibers. Here, we present functional evidence that the MYB83 transcription factor is another molecular switch in the SND1-mediated transcriptional network regulating secondary wall biosynthesis. MYB83 is specifically expressed in fibers and vessels where secondary wall thickening occurs. Its expression is directly activated by SND1 and its close homologs, including NST1, NST2, VND6 and VND7, indicating that MYB83 is their direct target. MYB83 overexpression is able to activate a number of the biosynthetic genes of cellulose, xylan and lignin and concomitantly induce ectopic secondary wall deposition. In addition, its overexpression upregulates the expression of several transcription factors involved in regulation of secondary wall biosynthesis. Dominant repression of MYB83 functions or simultaneous RNAi inhibition of MYB83 and MYB46 results in a reduction in secondary wall thickening in fibers and vessels and a deformation of vessels. Furthermore, double T-DNA knockout mutations of MYB83 and MYB46 cause a lack of secondary walls in vessels and an arrest in plant growth. Together, these results demonstrate that MYB83 and MYB46, both of which are SND1 direct targets, function redundantly in the transcriptional regulatory cascade leading to secondary wall formation in fibers and vessels.
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myb58 and myb63 are transcriptional activators of the lignin biosynthetic pathway during secondary cell wall formation in arabidopsis
The Plant Cell, 2009Co-Authors: Jianli Zhou, Ruiqin Zhong, Zhenghua YeAbstract:It has previously been shown that SECONDARY WALL–ASSOCIATED NAC DOMAIN PROTEIN1 (SND1) is a key transcription factor regulating secondary cell wall formation, including the biosynthesis of cellulose, xylan, and lignin. In this study, we show that two closely related SND1-regulated MYB transcription factors, MYB58 and MYB63, are transcriptional regulators specifically activating lignin biosynthetic genes during secondary wall formation in Arabidopsis thaliana. MYB58 and MYB63 are phylogenetically distinct from previously characterized MYBs shown to be associated with secondary wall formation or phenylpropanoid metabolism. Expression studies showed that MYB58 and MYB63 are specifically expressed in fibers and vessels undergoing secondary wall thickening. Dominant repression of their functions led to a reduction in secondary wall thickening and lignin content. Overexpression of MYB58 and MYB63 resulted in specific activation of lignin biosynthetic genes and concomitant ectopic deposition of lignin in cells that are normally unlignified. MYB58 was able to activate directly the expression of lignin biosynthetic genes and a secondary wall–associated laccase (LAC4) gene. Furthermore, the expression of MYB58 and MYB63 was shown to be regulated by the SND1 close homologs NST1, NST2, VND6, and VND7 and their downstream target MYB46. Together, our results indicate that MYB58 and MYB63 are specific transcriptional activators of lignin biosynthesis in the SND1-mediated transcriptional network regulating secondary wall formation.
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a battery of transcription factors involved in the regulation of secondary cell wall biosynthesis in arabidopsis
The Plant Cell, 2008Co-Authors: Ruiqin Zhong, Jianli Zhou, Ryan L Mccarthy, Zhenghua YeAbstract:SECONDARY WALL-ASSOCIATED NAC DOMAIN PROTEIN1 (SND1) is a master transcriptional switch activating the developmental program of secondary wall biosynthesis. Here, we demonstrate that a battery of SND1-regulated transcription factors is required for normal secondary wall biosynthesis in Arabidopsis thaliana. The expression of 11 SND1-regulated transcription factors, namely, SND2, SND3, MYB103, MYB85, MYB52, MYB54, MYB69, MYB42, MYB43, MYB20, and KNAT7 (a Knotted1-like homeodomain protein), was developmentally associated with cells undergoing secondary wall thickening. Of these, dominant repression of SND2, SND3, MYB103, MYB85, MYB52, MYB54, and KNAT7 significantly reduced secondary wall thickening in fiber cells. Overexpression of SND2, SND3, and MYB103 increased secondary wall thickening in fibers, and overexpression of MYB85 led to ectopic deposition of lignin in epidermal and cortical cells in stems. Furthermore, SND2, SND3, MYB103, MYB85, MYB52, and MYB54 were able to induce secondary wall biosynthetic genes. Direct target analysis using the estrogen-inducible system revealed that MYB46, SND3, MYB103, and KNAT7 were direct targets of SND1 and also of its close homologs, NST1, NST2, and vessel-specific VND6 and VND7. Together, these results demonstrate that a transcriptional network consisting of SND1 and its downstream targets is involved in regulating secondary wall biosynthesis in fibers and that NST1, NST2, VND6, and VND7 are functional homologs of SND1 that regulate the same downstream targets in different cell types.
Yolanda Chico - One of the best experts on this subject based on the ideXlab platform.
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Molecular and cellular insights into the role of SND1 in lipid metabolism.
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2020Co-Authors: Hiart Navarro-imaz, Yolanda Chico, Olatz Fresnedo, Begona Ochoa, Maria Jose Martinez, Itsaso Garcia-arcos, Yuri RuedaAbstract:Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an evolutionarily conserved protein present in eukaryotic cells from protozoa to mammals. SND1 has gained importance because it is overexpressed in aggressive cancer cells and diverse primary tumors. Indeed, it is regarded as a marker of cancer malignity. A broad range of molecular functions and the participation in many cellular processes have been attributed to SND1, mostly related to the regulation of gene expression. An increasing body of evidence points to a relevant relationship between SND1 and lipid metabolism. In this review, we summarize the knowledge about SND1 and its molecular and functional relationship with lipid metabolism. We highlight that SND1 plays a direct role in the regulation of cholesterol metabolism by affecting the activation of sterol response element-binding protein 2 (SREBP2) and we propose that that might have implications in the response of lipid homeostasis to stress situations.
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Insights Into SND1 Oncogene Promoter Regulation.
Frontiers in oncology, 2018Co-Authors: Begona Ochoa, Yolanda Chico, Maria Jose MartinezAbstract:The staphylococcal nuclease and Tudor domain containing 1 gene (SND1), also known as Tudor-SN, TSN or p100, encodes an evolutionarily conserved protein with invariant domain composition. SND1 contains four repeated staphylococcal nuclease domains and a single Tudor domain, which confer it endonuclease activity and extraordinary capacity for interacting with nucleic acids, individual proteins and protein complexes. Originally described as a transcriptional coactivator, SND1 plays fundamental roles in the regulation of gene expression, including RNA splicing, interference, stability, and editing, as well as in the regulation of protein and lipid homeostasis. Recently, SND1 has gained attention as a potential disease biomarker due to its positive correlation with cancer progression and metastatic spread. Such functional diversity of SND1 marks this gene as interesting for further analysis in relation with the multiple levels of regulation of SND1 protein production. In this review, we summarize the SND1 genomic region and promoter architecture, the set of transcription factors that can bind the proximal promoter, and the evidence supporting transactivation of SND1 promoter by a number of signal transduction pathways operating in different cell types and conditions. Unraveling the mechanisms responsible for SND1 promoter regulation is of utmost interest to decipher the SND1 contribution in the realm of both normal and abnormal physiology.
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Channeling of newly synthesized fatty acids to cholesterol esterification limits triglyceride synthesis in SND1-overexpressing hepatoma cells.
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2018Co-Authors: Hiart Navarro-imaz, Yolanda Chico, Yuri Rueda, Olatz FresnedoAbstract:Abstract SND1 is a putative oncoprotein whose molecular function remains unclear. Its overexpression in hepatocellular carcinoma impairs cholesterol homeostasis due to the altered activation of the sterol regulatory element-binding protein (SREBP) 2, which results in the accumulation of cellular cholesteryl esters (CE). In this work, we explored whether high cholesterol synthesis and esterification originates changes in glycerolipid metabolism that might affect cell growth, given that acetyl-coenzyme A is required for cholesterogenesis and fatty acids (FA) are the substrates of acyl-coenzyme A:cholesterol acyltransferase (ACAT). SND1-overexpressing hepatoma cells show low triglyceride (TG) synthesis, but phospholipid biosynthesis or cell growth is not affected. Limited TG synthesis is not due to low acetyl-coenzyme A or NADPH availability. We demonstrate that the main factor limiting TG synthesis is the utilization of FAs for cholesterol esterification. These metabolic adaptations are linked to high Scd1 expression, needed for the de novo production of oleic acid, the main FA used by ACAT. We conclude that high cholesterogenesis due to SND1 overexpression might determine the channeling of FAs to CEs.
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srebp 2 driven transcriptional activation of human SND1 oncogene
Oncotarget, 2017Co-Authors: Sandra Armengol, Yolanda Chico, Enara Arretxe, Leire Enzunza, Irati Llorente, Unai Mendibil, Hiart Navarroimaz, Begona Ochoa, Maria Jose MartinezAbstract:Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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SREBP-2-driven transcriptional activation of human SND1 oncogene.
Oncotarget, 2017Co-Authors: Sandra Armengol, Hiart Navarro-imaz, Yolanda Chico, Enara Arretxe, Leire Enzunza, Irati Llorente, Unai Mendibil, Begona Ochoa, Maria Jose MartinezAbstract:// Sandra Armengol 1 , Enara Arretxe 1 , Leire Enzunza 1 , Irati Llorente 1 , Unai Mendibil 1 , Hiart Navarro-Imaz 1 , Begona Ochoa 1 , Yolanda Chico 1 and Maria Jose Martinez 1 1 Lipids & Liver Research Group, Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Vizcaya, Spain Correspondence to: Maria Jose Martinez, email: mariajose.martinez@ehu.eus Keywords: SND1; Tudor-SN; gene promoter regulation; SREBP-2; SREBP-1 Received: January 04, 2017 Accepted: September 22, 2017 Published: November 21, 2017 ABSTRACT Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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Molecular and cellular insights into the role of SND1 in lipid metabolism.
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2020Co-Authors: Hiart Navarro-imaz, Yolanda Chico, Olatz Fresnedo, Begona Ochoa, Maria Jose Martinez, Itsaso Garcia-arcos, Yuri RuedaAbstract:Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an evolutionarily conserved protein present in eukaryotic cells from protozoa to mammals. SND1 has gained importance because it is overexpressed in aggressive cancer cells and diverse primary tumors. Indeed, it is regarded as a marker of cancer malignity. A broad range of molecular functions and the participation in many cellular processes have been attributed to SND1, mostly related to the regulation of gene expression. An increasing body of evidence points to a relevant relationship between SND1 and lipid metabolism. In this review, we summarize the knowledge about SND1 and its molecular and functional relationship with lipid metabolism. We highlight that SND1 plays a direct role in the regulation of cholesterol metabolism by affecting the activation of sterol response element-binding protein 2 (SREBP2) and we propose that that might have implications in the response of lipid homeostasis to stress situations.
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Insights Into SND1 Oncogene Promoter Regulation.
Frontiers in oncology, 2018Co-Authors: Begona Ochoa, Yolanda Chico, Maria Jose MartinezAbstract:The staphylococcal nuclease and Tudor domain containing 1 gene (SND1), also known as Tudor-SN, TSN or p100, encodes an evolutionarily conserved protein with invariant domain composition. SND1 contains four repeated staphylococcal nuclease domains and a single Tudor domain, which confer it endonuclease activity and extraordinary capacity for interacting with nucleic acids, individual proteins and protein complexes. Originally described as a transcriptional coactivator, SND1 plays fundamental roles in the regulation of gene expression, including RNA splicing, interference, stability, and editing, as well as in the regulation of protein and lipid homeostasis. Recently, SND1 has gained attention as a potential disease biomarker due to its positive correlation with cancer progression and metastatic spread. Such functional diversity of SND1 marks this gene as interesting for further analysis in relation with the multiple levels of regulation of SND1 protein production. In this review, we summarize the SND1 genomic region and promoter architecture, the set of transcription factors that can bind the proximal promoter, and the evidence supporting transactivation of SND1 promoter by a number of signal transduction pathways operating in different cell types and conditions. Unraveling the mechanisms responsible for SND1 promoter regulation is of utmost interest to decipher the SND1 contribution in the realm of both normal and abnormal physiology.
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srebp 2 driven transcriptional activation of human SND1 oncogene
Oncotarget, 2017Co-Authors: Sandra Armengol, Yolanda Chico, Enara Arretxe, Leire Enzunza, Irati Llorente, Unai Mendibil, Hiart Navarroimaz, Begona Ochoa, Maria Jose MartinezAbstract:Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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SREBP-2-driven transcriptional activation of human SND1 oncogene.
Oncotarget, 2017Co-Authors: Sandra Armengol, Hiart Navarro-imaz, Yolanda Chico, Enara Arretxe, Leire Enzunza, Irati Llorente, Unai Mendibil, Begona Ochoa, Maria Jose MartinezAbstract:// Sandra Armengol 1 , Enara Arretxe 1 , Leire Enzunza 1 , Irati Llorente 1 , Unai Mendibil 1 , Hiart Navarro-Imaz 1 , Begona Ochoa 1 , Yolanda Chico 1 and Maria Jose Martinez 1 1 Lipids & Liver Research Group, Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Vizcaya, Spain Correspondence to: Maria Jose Martinez, email: mariajose.martinez@ehu.eus Keywords: SND1; Tudor-SN; gene promoter regulation; SREBP-2; SREBP-1 Received: January 04, 2017 Accepted: September 22, 2017 Published: November 21, 2017 ABSTRACT Upregulation of Staphylococcal nuclease and tudor domain containing 1 (SND1) is linked to cancer progression and metastatic spread. Increasing evidence indicates that SND1 plays a role in lipid homeostasis. Recently, it has been shown that SND1-overexpressing hepatocellular carcinoma cells present an increased de novo cholesterol synthesis and cholesteryl ester accumulation. Here we reveal that SND1 oncogene is a novel target for SREBPs. Exposure of HepG2 cells to the cholesterol-lowering drug simvastatin or to a lipoprotein-deficient medium triggers SREBP-2 activation and increases SND1 promoter activity and transcript levels. Similar increases in SND1 promoter activity and mRNA are mimicked by overexpressing nuclear SREBP-2 through expression vector transfection. Conversely, SREBP-2 suppression with specific siRNA or the addition of cholesterol/25-hydroxycholesterol to cell culture medium reduces transcriptional activity of SND1 promoter and SND1 mRNA abundance. Chromatin immunoprecipitation assays and site-directed mutagenesis show that SREBP-2 binds to the SND1 proximal promoter in a region containing one SRE and one E-box motif which are critical for maximal transcriptional activity under basal conditions. SREBP-1, in contrast, binds exclusively to the SRE element. Remarkably, while ectopic expression of SREBP-1c or -1a reduces SND1 promoter activity, knocking-down of SREBP-1 enhances SND1 mRNA and protein levels but failed to affect SND1 promoter activity. These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. We anticipate the contribution of a SREBPs/SND1 pathway to lipid metabolism reprogramming of human hepatoma cells.
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profiling of promoter occupancy by the SND1 transcriptional coactivator identifies downstream glycerolipid metabolic genes involved in tnfα response in human hepatoma cells
Nucleic Acids Research, 2015Co-Authors: Enara Arretxe, Yolanda Chico, Sandra Armengol, Begona Ochoa, Sarai Mula, Maria Jose MartinezAbstract:The NF-κB-inducible Staphylococcal nuclease and tudor domain-containing 1 gene (SND1) encodes a coactivator involved in inflammatory responses and tumorigenesis. While SND1 is known to interact with certain transcription factors and activate client gene expression, no comprehensive mapping of SND1 target genes has been reported. Here, we have approached this question by performing ChIP-chip assays on human hepatoma HepG2 cells and analyzing SND1 binding modulation by proinflammatory TNFα. We show that SND1 binds 645 gene promoters in control cells and 281 additional genes in TNFα-treated cells. Transcription factor binding site analysis of bound probes identified motifs for established partners and for novel transcription factors including HSF, ATF, STAT3, MEIS1/AHOXA9, E2F and p300/CREB. Major target genes were involved in gene expression and RNA metabolism regulation, as well as development and cellular metabolism. We confirmed SND1 binding to 21 previously unrecognized genes, including a set of glycerolipid genes. Knocking-down experiments revealed that SND1 deficiency compromises the glycerolipid gene reprogramming and lipid phenotypic responses to TNFα. Overall, our findings uncover an unexpected large set of potential SND1 target genes and partners and reveal SND1 to be a determinant downstream effector of TNFα that contributes to support glycerophospholipid homeostasis in human hepatocellular carcinoma during inflammation.
