Dataset Information

The CKS1/CKS2 proteostasis axis is crucial to maintain hematopoietic stem cell function

ABSTRACT: Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification and degradation – broadly termed protein homeostasis or “proteostasis” – in these cells is still in its infancy. Here we report the requirement of the small phospho-binding adaptor proteins, the cyclin dependent kinase subunits (Cks1 and Cks2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. Cks1 and Cks2 are critical regulators of a myriad of key intracellular signalling pathways that govern hematopoietic stem cell biology and together they balance protein homeostasis and restrain reactive oxygen species to ensure healthy hematopoietic stem cell function.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Haematopoietic Stem Cells

SUBMITTER: Pedro Casado-Izquierdo

LAB HEAD: Pedro R. Cutillas

PROVIDER: PXD035984 | Pride | 2023-03-11

REPOSITORIES: Pride

ACCESS DATA

Publications

The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function.

Grey William W Atkinson Samantha S Rix Beatrice B Casado Pedro P Ariza-McNaughton Linda L Hawley Cathy C Sopoena Miriam L ML Bridge Katherine S KS Kent David D Cutillas Pedro R PR Bonnet Dominique D

HemaSphere 20230228 3

Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation-broadly termed protein homeostasis or "proteostasi ...[more]

PMID: 36874381

Similar Datasets

Project description:Preclinical studies of primary cancer cells are always done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3-10% range, with most tumors in an hypoxic or 1-2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anti-cancer agents is routinely examined at ambient O2. Here, using both mouse models and human cancers, we demonstrate that tumors collected, processed and propagated at physiologic (physioxia) O2 compared to ambient air display very distinct differences in key signaling networks including Lgr5/Wnt, Yap, and Nrf2/Keap1, nuclear reactive oxygen species levels, alternative splicing, and sensitivity to several targeted therapies including PIK3CAalpha-specific and EGFR inhibitors. Significance: Extra-physiologic oxygen shock/stress (EPHOSS), as noted in cells collected/processed under ambient air, has been demonstrated to have significant impact on numbers and engrafting ability of hematopoietic stem cells. We report deleterious effects of EPHOSS on cancer cell behavior and EPHOSS-mediated effects on cancer cells give misleading information on signaling pathway activation that could severely impact the relevance of these findings. Cancer cells under EPHOSS show higher proliferation rate compared to cells under physioxia and thus are sensitive to anti-proliferative agents. Thus, drugs that show effectiveness on cancer cells collected in ambient air and subjected to EPHOSS may not be effective or as relevant in vivo, results that could partially explain the limited clinical translation of laboratory findings. Evaluating cell signaling and effects of drugs on cancer cells under physiologic O2 prior to in vivo studies could substantially reduce cost and aid in drug discovery relevant to the actual physioxia/pathological status of the tumor cells in vivo.

Dataset Information

The CKS1/CKS2 proteostasis axis is crucial to maintain hematopoietic stem cell function

Publications

The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure