The tumor suppressor PTEN regulates negatively Sertoli cell proliferation, testis size and sperm production in vivo
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PROVIDER: PRJNA507599 | ENA |
REPOSITORIES: ENA
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2019-01-02 | GSE123119 | GEO
Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect.
2012-12-01 | GSE35670 | GEO
Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.
2012-12-01 | E-GEOD-35670 | biostudies-arrayexpress
Project description:PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We show that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels, while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data show that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatmtreatingwith PTEN mutant melanoma.
2023-03-09 | GSE210359 | GEO
Project description:Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The Class III PI3K, PIK3C3/VPS34 plays key roles in endosomal membrane traffic and macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which Pik3c3 was specifically deleted in Sertoli cells (cKO) and found that after one round of normal spermatogenesis, the cKO mice quickly became infertile and showed disruption of Sertoli cell polarity, loss of germ cells and impaired spermiogenesis. Subsequent proteomics and phosphoproteomics analyses enriched the F-actin cytoskeleton network involved in the disorganized Sertoli-cell structure in cKO testis, and showed significantly increased expression of the F-actin negative regulator SCIN and reduced phosphorylation of the α-tubulin deacetylase HDAC6. Our results further demonstrated that the accumulation of SCIN in cKO Sertoli cells caused the disassembly of the F-actin cytoskeleton, which was related to the failure of SCIN degradation through the autophagy-lysosome pathway. Additionally, we found that the phosphorylation of HDAC6 at site S59 by PIK3C3 was essential for its degradation through the ubiquitin-proteasome pathway. As a result, the HDAC6 that accumulated in cKO Sertoli cells deacetylated SCIN at site K189 and led to a disorganized F-actin cytoskeleton. Taken together, our findings elucidate the indispensable role of PIK3C3 in maintaining Sertoli cell polarity and reveal a new mechanism in which both its protein kinase activity and its regulation of autophagy are required for the stabilization of the actin cytoskeleton.
2024-08-09 | PXD036242 | Pride
Project description:Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The Class III PI3K, PIK3C3/VPS34 plays key roles in endosomal membrane traffic and macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which Pik3c3 was specifically deleted in Sertoli cells (cKO) and found that after one round of normal spermatogenesis, the cKO mice quickly became infertile and showed disruption of Sertoli cell polarity, loss of germ cells and impaired spermiogenesis. Subsequent proteomics and phosphoproteomics analyses enriched the F-actin cytoskeleton network involved in the disorganized Sertoli-cell structure in cKO testis, and showed significantly increased expression of the F-actin negative regulator SCIN and reduced phosphorylation of the α-tubulin deacetylase HDAC6. Our results further demonstrated that the accumulation of SCIN in cKO Sertoli cells caused the disassembly of the F-actin cytoskeleton, which was related to the failure of SCIN degradation through the autophagy-lysosome pathway. Additionally, we found that the phosphorylation of HDAC6 at site S59 by PIK3C3 was essential for its degradation through the ubiquitin-proteasome pathway. As a result, the HDAC6 that accumulated in cKO Sertoli cells deacetylated SCIN at site K189 and led to a disorganized F-actin cytoskeleton. Taken together, our findings elucidate the indispensable role of PIK3C3 in maintaining Sertoli cell polarity and reveal a new mechanism in which both its protein kinase activity and its regulation of autophagy are required for the stabilization of the actin cytoskeleton.
2024-08-09 | PXD036240 | Pride
Project description:Vitamin C (ascorbic acid, AA), as essential micro-nutrient and antioxidant, can affect multiple cellular processes. Previously, we showed that Vitamin C supplement could promote the proliferation and suppress apoptosis of porcine Sertoli cells, via modulating the global nucleic acid methylation levels to alter transcriptome and proteomics. Due to the differences between pig and rodent species, here we investigated the effects of Vitamin C on mouse TM4 Sertoli cells. Vitamin C (250µM) treatment of mouse TM4 Sertoli cells for 36h could significantly increase cell viability, promote cell proliferation and decrease the cell percentage with early apoptosis. Vitamin C (250µM, 36h) also significantly decreased ROS level, elevated mitochondrial function, altered the levels of nucleic acid N6-methylation (m6A) and modified the levels of histone H3 trimethylation (H3K4me3, H3K9Me3 and H3K36me3) of mouse TM4 Sertoli cells. Vitamin C (250µM, 36h) promoted the secretion of anti-müllerian hormone and Estrodiol, but decreased lactate metabolite in mouse TM4 Sertoli cells. RNA-seq identified 112 differentially expressed genes (DEGs) (74 up- and 38 down-regulated) (P≤0.05, |log2Fold Change|≥1) as induced by Vitamin C in mouse TM4 Sertoli cells. Gene enrichment analysis found multiple significantly enriched biological terms or pathways, including GO terms of regulation of response to biotic stimulus, homeostasis of number of cells, positive regulation of tumor necrosis factor production, GTPase activity, calmodulin binding etc., and KEGG signal pathways of calcium signal pathway, cGMP-PKG signaling pathway, steroid biosynthesis, arginine biosynthesis etc. 9 DEGs were selected for RT-qPCR validation and 8 of them showed the change trend consistent to RNA-seq. Taken together, Vitamin C (250µM, 36h) could modulate the functions of mouse TM4 Sertoli cells, through modifying the transcriptome to affect multiple signal pathways.
2024-07-31 | GSE241623 | GEO
Project description:Environmental toxicant induced epigenetic transgenerational inheritance has been shown to affect testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome that are associated with the onset of testis disease.
2018-11-08 | GSE118306 | GEO
Project description:Stable activation of the WNT signaling effector beta-catenin (CTNNB1(ex3) in ovarian granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life. Loss of the tumor suppressor gene Pten accelerates GCT formation in the CTNNB1 strain. Conversely, expression of oncogenic KRASG12D causes the dramatic arrest of proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice developed early-onset GCTs leading to premature death in a manner similar to theCtnnb1;Pten mutant mice. Moreover, the GCTs in the Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation. Microarray and RT-PCR analyses revealed that ovaries from mice expressing dominant-stable CTNNB1 with either Pten loss or KRAS activation were unpredictably similar. Specifically, gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. Furthermore, the concomitant activation of CTNNB1 and KRAS in Sertoli cells resulted in the development of granulosa cell tumors of the testis. RT-PCR studies showed a partial overlap in gene regulatory processes associated with tumor development in the ovary and testis. Together, these results suggest that KRAS activation and Pten loss induce GCT development from premalignant lesions via highly similar molecular mechanisms. four samples: average of two wild type samples (previously submitted as GSM403220 and GSM403221), beta-Catenin constitutively active mutant, beta-Catenin;Pten double mutant, and beta-Catenin;Kras(G12D) double mutant
2011-09-19 | E-GEOD-27656 | biostudies-arrayexpress
Project description:Spermatogenesis requires the presence of functional somatic Sertoli cells in the seminiferous tubules of the testis. Sertoli cells provide support and factors necessary for the successful progression of germ cells into spermatozoa. Sertoli cells are regulated to a large degree by the glycoprotein hormone FSH, which is required for the testis to acquire full size and spermatogenic capacity. Signaling events initiated by the binding of FSH to its receptor lead to an alteration of Sertoli cell gene expression. To characterize the changes in gene expression in FSH-treated Sertoli cells, we used the mRNA from these cells to screen Affymetrix U34A rat GeneChip oligonucleotide microarrays. Sertoli cells from 20-d-old rats were cultured in the presence of 25 ng/ml ovine FSH. At 0, 2, 4, 8, and 24 h after the addition of FSH, total RNA was purified and used to prepare biotinylated target, which was hybridized to the U34A rat microarray containing approximately 9000 rat genes. Analysis identified 100-300 transcripts at each time point that were up-regulated or down-regulated by 2-fold or greater. Genes previously reported to be FSH or cAMP regulated in rat Sertoli cells were identified, in addition to numerous genes not reported to be expressed or FSH regulated in Sertoli cells. The expression patterns of five of these genes, encoding nerve growth factor inducible gene B, PRL-1, PC3 nerve growth factor-inducible antiproliferative putative secreted protein, diacylglycerol acyltransferase, and an expressed sequence tag, in FSH- and N,O'-dibutyryl cAMP-treated rat Sertoli cells were confirmed and characterized by Northern blot analysis. Thus, we have begun to define the transcriptome induced and repressed by FSH in rat Sertoli cells, and we have generated datasets of genes available for further analysis in regard to spermatogenesis and Sertoli cell signaling. Keywords: other
2003-07-16 | GSE509 | GEO