Revealing different roles of the mTOR-targets S6K1 and S6K2 in breast cancer by expression profiling and structural analysis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75813 | GEO | 2015/12/09
SECONDARY ACCESSION(S): PRJNA305419
REPOSITORIES: GEO
Similar Datasets
Project description:Expression profiles of ZR751 breast cancer cells after downregulation of S6K1, S6K2 and S6K1+S6K2. Triplicates of control, S6K1siRNA, S6K2siRNA and S6K1+S6K2siRNA, in total twelve samples.
2015-12-09 | E-GEOD-75813 | biostudies-arrayexpress
Project description:BackgroundThe AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.Materials and methodsWhole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.ResultsGenome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.
| S-EPMC4689523 | biostudies-literature
Project description:The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.
| S-EPMC7072743 | biostudies-literature
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE214339 | GEO
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE214340 | GEO
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE232448 | GEO
Project description:To systematically identify the function of S6K1 and S6K2 in glioblastoma cells, LN229 cells were stably transduced with Cas9, control non-targeting sgRNA (sgNT), or sgRNAs targeting S6K1 or S6K2. The cells were then transiently transfected with non-targeting siRNAs (siNT), or siRNA pools targeting S6K1 or S6K2. RNA sequencing was performed to compare cellular responses to inactivation of single or combination S6 kinases.
2024-08-28 | GSE196591 | GEO
Project description:Loss of Tsc1 in the kidneys gives rise to rapid polycystogenesis and kidney failure due to the hyperactivation of mTOR complex I (mTORC1). One of the major downstream targets of mTORC1 is S6K1, which is responsible for driving many of the effector functions of mTOR. Strikingly, the loss of S6k1 in the context of hyperactivated mTOR is sufficient to reverse the generation of polycystic kidneys. In an effort to uncover novel direct S6k1 substrates involved in the generation of cystic kidneys, we generated Tsc1-null and Tsc1/S6k1-double null murine inner medullary collecting duct (iMCD3) cell lines using CRISPR/Cas9. Using these two cell lines, we conducted a phosphoproteome screen to search for novel candidates. Using a combination of antibody-motif enrichment and metal affinity enrichment, we provide a comprehensive phosphoproteome profile between these two genotypes.
2020-08-11 | PXD014832 | Pride
Project description:Imbalanced mTORC1-S6K1 engages signalling cascades related to obesity and fatty liver. Here, we set up to assess the therapeutic blockage of the ribosomal protein S6 kinase 1 (S6K1) in diet-induced obese (DIO) mice challenged with LY2584702 (LY) tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumours. To characterize the ability of LY in counteracting obesity and diet-induced disturbances, DIO male mice were challenged every 12 h by oral gavage with LY in treatments lasting 12 and 4 weeks. We show that diminished S6K1 activity in mice treated with LY hampers fat mass expansion and ameliorates dyslipidaemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver performance. Accordingly, impaired mTORC1 signalling in fat (decreased) and liver (increased) co-segregated with defective epithelial-mesenchymal transition, being prominent a decreased expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures, while hypertriglyceridemia and hepatic steatosis were improved in treatments of 12 and 4 weeks. This study provides new insights into the therapeutic intervention of S6K1 signalling, and opens a promising avenue for prevalent metabolic diseases.
2022-08-01 | GSE193028 | GEO
Project description:We examined the transcript changes in long-lived S6K1-/- female mice compared to wild type controls.
2009-09-04 | E-MEXP-2320 | biostudies-arrayexpress