CDK4 Inactivation Hinders Cell Death and Metabolism Remodeling Mitochondria-ER contacts in Triple-Negative Breast cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1167725 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30853718.fastq.gz | Fastqsanger.gz | |||
| SRR30853719.fastq.gz | Fastqsanger.gz | |||
| SRR30853720.fastq.gz | Fastqsanger.gz | |||
| SRR30853721.fastq.gz | Fastqsanger.gz | |||
| SRR30853722.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:The shift in the energetic demands of proliferating cells during tumorigenesis requires extensive crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Here, using both genetic and pharmacological approaches, we sought to determine the metabolic role of CDK4 in triple-negative breast cancer (TNBC) cells. Unexpectedly, the deletion of CDK4 only modestly reduced TNBC cell proliferation and did not hinder tumor formation in vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells upon CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERC) formation, thereby promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. Such CDK4-mediated mitochondrial calcium signaling is required for the metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance by inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting of MERCs-associated metabolic shifts.
2024-10-14 | GSE278524 | GEO
Project description:Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by rough-Endoplasmic Reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated-mitochondria are analyzed by transcriptomics, proteomics and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.
2021-03-15 | GSE134777 | GEO
Project description:Organelles such as endoplasmic reticulum (ER) and mitochondria interact with each other at specialized domains on the ER known as mitochondria-associated membranes (MAMs). Here, using three-dimensional high-resolution imaging techniques, we show that the Sel1LHrd1 protein complex, the most conserved branch of ER-associated protein degradation (ERAD), exerts a profound impact on ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover and hence the abundance of the MAM protein sigma receptor 1 (SigmaR1). Sel1L or Hrd1 deficiency in brown adipocytes impairs dynamic interaction between ER and mitochondria, leading to the formation of pleomorphic “megamitochondria” and, in some cases with penetrating ER tubule(s), in response to acute cold challenge. Mice with ERAD deficiency are cold sensitive and exhibit mitochondrial dysfunction in brown adipocytes. Mechanistically, endogenous SigmaR1 is targeted for proteasomal degradation by Sel1L-Hrd1 ERAD, whose accumulation in ERAD-deficient cells leads to mitofusin 2 (Mfn2) oligomerization, thereby linking ERAD to mitochondrial dynamics. Our study identifies Sel1L-Hrd1 ERAD as a critical determinant of ER-mitochondria contacts, thereby regulating mitochondrial dynamics and thermogenesis.
2020-04-24 | GSE145895 | GEO
Project description:Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also directly regulate systemic cellular activities, remains unknown. Here, we report the ultrastructural organization and dynamics of a new type of inter-organelle contact which is formed by rough-Endoplasmic Reticulum that is closely wrapped around the mitochondrion (wrappER). To elucidate the in vivo function of this inter-organelle association, mouse liver fractions enriched in wrappER-associated-mitochondria were analyzed in parallel by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to an unexpected role in the biogenesis of very-low-density lipoproteins (VLDLs). Altering wrappER-mitochondria contacts curtails liver VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, mirrors this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The participation of liver wrappER-mitochondria contacts in VLDL biology reveals a role of inter-organelle contacts in systemic lipid homeostasis.
2021-03-15 | PXD021826 | Pride
Project description:Mitochondria-Rough-ER Contacts in The Liver Regulate Systemic Lipid Homeostasis
| PRJNA556401 | ENA
Project description:Increase in ER-mitochondria contacts and mitochondrial fusion are hallmarks of mitochondrial activation during embryogenesis
| PRJNA1111056 | ENA
Project description:Regulation of endoplasmic reticulum-mitochondria contacts and mitochondrial dynamics by Sel1L-Hrd1 ERAD during thermogenesis
| PRJNA608688 | ENA
Project description:Impact of CDK4-deficiency on EM-BM-5-myc driven B-lymphoma By crossing mating CDK4 Knockout mice with EM-BM-5-myc mice,We found CDK4-deficiency enhances the EM-BM-5-myc induced B-lymphoma.We further to discover the molecular mechanism B-lymphoma cells form the cdk4+/+ EM-BM-5-myc and cdk4-/-EM-BM-5-myc mice and then culturing for RNA extraction and hybridization on Affymetrix microarrays.
2012-12-16 | E-GEOD-21683 | biostudies-arrayexpress
Project description:Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors have emerged as a major obstacle that hinders their utility beyond ER+ breast cancer. Palbociclib-sensitive ER+ breast cancer models and pancreatic ductal adenocarcinoma (PDAC) models were employed to identify functional determinants of response. In all models tested the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity. While depleting CDK4 and 6 was sufficient to limit proliferation in specific resistance setting, RB loss renders cells completely CDK4/6 independent. The main down-stream target in this context is the activation status of CDK2 which is suppressed with CDK4/6 inhibition in an RB-dependent fashion. The P27KIP1 protein levels are associated with plasticity/rigidity of the cell cycle and correlates with sensitivity to CDK4/6 inhibiion. Exogenous overexpression and pharmacological induction of P27KIP1 by targeting the MEK/ERK pathway enhances the cytostatic effect of palbociclib. Similar to cell-culture data, in vivo experiments revealed that combination treatment of palbociclib and trametinib in mice bearing PDAC PDXs elicited a robust anti-proliferative effect with a corresponding increase in p27 expression. Mice bearing MCF7 xenografts displayed a durable response in the presence of palbociclib; however, over the course of treatment few cells begin to evade the negative cell-cycle regulation. Based on multispectral staining, the MCF7 tumor cells that underwent RB inactivation in the presence of palbociclib harbored low p27 expression. Finally, we demonstrate that the cell-cycle plasticity that enables tumor models to evade the palbociclib mediated RB activation could be potently targeted using a clinically applicable CDK2 inhibitor.
2020-06-30 | GSE146788 | GEO
Project description:Skeletal muscle function is vital to movement, thermogenesis and metabolism. Muscle fibers differ in contractile ability, mitochondrial content and metabolic properties and muscle fiber transition influences muscle function. However, the molecular mechanisms regulating muscle fiber transition in muscle function are unclear. Here, in over 150 human muscle samples, we observed that markers of oxidative muscle fiber and mitochondria correlate positively with PPARGC1 and CDK4, and, negatively with CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing an overactive Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, are longer, leaner, exhibit increased oxidative myofibers with superior mitochondrial energetics, display enhanced muscle glucose uptake, and are protected from obesity and diabetes. In contrast, Cdk4-deficiency, or skeletal muscle-specific deletion of Cdk4’s transcriptional target, E2F3, reduces oxidative myofiber numbers, deteriorates mitochondrial function and exercise capacity, while increasing diabetes susceptibility. E2F3 activates the PPARGC1 promoter and CDK4/E2F3/PPARGC1 levels correlate positively with exercise and fitness, and negatively with adiposity, insulin resistance and lipid accumulation in muscle. These findings provide insight into oxidative muscle fiber transition and function that is of relevance to metabolic and muscular diseases.
2023-07-06 | GSE185154 | GEO