ArticleNature communications2015
Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells.
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Article in Nature communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
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31 citing papers in PubMed, 53 citations in OpenAlex.
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- Cyclin-dependent kinase inhibitors in malignant hematopoiesis.Frontiers in oncology · 2022Review
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- The distinct effects of P18 overexpression on different stages of hematopoiesis involve TGF-β and NF-κB signaling.Scientific reports · 2021Article
- Understanding the "SMART" features of hematopoietic stem cells and beyond.Science China. Life sciences · 2021Review
- Enhanced self-renewal of human long-term hematopoietic stem cells by a sulfamoyl benzoate derivative targeting p18INK4C.Blood advances · 2021Article
- Targeted stabilization of Munc18-1 function via pharmacological chaperones.EMBO molecular medicine · 2021Article
- Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence.Frontiers in cell and developmental biology · 2021Article
- Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34Stem cells translational medicine · 2020Article
- Combination of SB431542, Chir9901, and Bpv as a novel supplement in the culture of umbilical cord blood hematopoietic stem cells.Stem cell research & therapy · 2020Article
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Authors and funding
24 authors at 4 institutions in 2 countries.
Yingdai GaoState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Peng Yang1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Hongmei ShenDepartment of Radiation Oncology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Hui YuDepartment of Radiation Oncology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Xianmin SongDepartment of Hematology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, China.
Liyan ZhangState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Peng Zhang1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.ORCID 0000000155740899
Haizi Cheng1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Zhaojun Xie1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Sha HaoState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Fang DongState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Shihui MaState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Qing JiState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Patrick Bartlow1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Yahui DingState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Lirong Wang1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Haibin Liu1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Yanxin LiState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Hui ChengState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Weimin MiaoState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Weiping YuanState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Youzhong YuanState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Tao ChengState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.ORCID 0000000343951095
Xiang-Qun Xie1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Chinese Academy of Medical Sciences & Peking Union Medical College · CNNational Institute on Drug Abuse · USUPMC Hillman Cancer Center · USSecond Military Medical University · CN
Funding
VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JOHN C. BYRD · 1988 to 2026
$158.0MUniversity of Pittsburgh Clinical and Translational Science InstituteUL1TR000005 · NCATS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI REIS, STEVEN E · 2012 to 2015
$50.8MNIDA Center of Excellence OF Computational Drug Abuse Research (CDAR)P30DA035778 · NIDA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BAHAR, IVET, XIE, XIANG-QUN · 2014 to 2018
$5.4MStructure/Function of the CB2 Receptor Binding and G-protein Recognition PocketsR01DA025612 · NIDA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI XIE, XIANG-QUN · 2010 to 2014
$1.7MScreen and Design p18 Chemical Probes for Hematopoietic Stem Cell Self-RenewalR21HL109654 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI XIE, XIANG-QUN · 2011 to 2012
$413kNCATS NIH HHS UL1 TR000005NCI NIH HHS P30 CA047904NHLBI NIH HHS NIH R21HL1096541NHLBI NIH HHS R21 HL109654NIDA NIH HHS P30 DA035778NIDA NIH HHS R01 DA025612
Abstract
Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.
Indexed as
Cell Culture TechniquesGene Expression RegulationAnimalsApoptosisCell CycleCell ProliferationCell SeparationCoculture TechniquesCyclin-Dependent Kinase 6Cyclin-Dependent Kinase Inhibitor p18Cyclin-Dependent Kinase Inhibitor p27FemaleGene DeletionHematopoietic Stem CellsMaleMiceCdk6 protein, mouseCdkn1b protein, mouseCdkn2c protein, mouseCyclin-Dependent Kinase 6Cyclin-Dependent Kinase Inhibitor p18Cyclin-Dependent Kinase Inhibitor p27
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