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  1. Article ; Online: Guarding the guardian: Mdmx plays important roles in setting p53 basal activity and determining biological responses in vivo.

    Wang, Yunyuan V / Wade, Mark / Wahl, Geoffrey M

    Cell cycle (Georgetown, Tex.)

    2009  Volume 8, Issue 21, Page(s) 3443–3444

    MeSH term(s) Animals ; DNA Damage/physiology ; Mice ; Mice, Mutant Strains ; Phosphorylation ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin Thiolesterase/metabolism
    Chemical Substances Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Ubiquitin Thiolesterase (EC 3.4.19.12)
    Language English
    Publishing date 2009-11-06
    Publishing country United States
    Document type Editorial
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.8.21.9744
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The p53 orchestra: Mdm2 and Mdmx set the tone.

    Wade, Mark / Wang, Yunyuan V / Wahl, Geoffrey M

    Trends in cell biology

    2010  Volume 20, Issue 5, Page(s) 299–309

    Abstract: The activities of p53 cover diverse aspects of cell biology, including cell cycle control, apoptosis, metabolism, fertility, differentiation and cellular reprogramming. Although loss of p53 function engenders tumor susceptibility, hyperactivation of p53 ... ...

    Abstract The activities of p53 cover diverse aspects of cell biology, including cell cycle control, apoptosis, metabolism, fertility, differentiation and cellular reprogramming. Although loss of p53 function engenders tumor susceptibility, hyperactivation of p53 is lethal. Therefore, p53 activity must be strictly regulated to maintain normal tissue homeostasis. Critical for the control of p53 function are its two main negative regulators: Mdm2 and Mdmx. Recent reports have provided insight into the complex mechanisms that regulate these two proteins and have revealed novel functions for each. Here, we review and evaluate models of Mdm2- and Mdmx-dependent regulation of p53 activity. Both Mdm2 and Mdmx receive input from numerous signaling pathways and interact with many proteins in addition to p53. Therefore, we also consider roles for Mdm2 and Mdmx in additional cancer-related networks, including Notch signaling and the epithelial-to-mesenchymal transition.
    MeSH term(s) Animals ; Cell Cycle Proteins ; Humans ; Models, Biological ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ubiquitination
    Chemical Substances Cell Cycle Proteins ; MDM4 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2010-02-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 30122-x
    ISSN 1879-3088 ; 0962-8924
    ISSN (online) 1879-3088
    ISSN 0962-8924
    DOI 10.1016/j.tcb.2010.01.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: AMP-Activated Protein Kinase Induces p53 by Phosphorylating MDMX and Inhibiting Its Activity

    He, Guifen / Zhang, Yi-Wei / Lee, Jun-Ho / Zeng, Shelya X. / Wang, Yunyuan V. / Luo, Zhijun / Dong, X. Charlie / Viollet, Benoit / Wahl, Geoffrey M. / Lü, Hua

    Molecular and Cellular Biology. 2014 Jan. 1, v. 34, no. 2 p.148-157

    2014  

    Abstract: AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in ... ...

    Abstract AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in vitro and in cells, leading to enhanced association between MDMX and 14-3-3. This markedly inhibits p53 ubiquitylation and significantly stabilizes and activates p53. By striking contrast, no phosphorylation of MDM2 by AMPK was noted. AMPK-mediated MDMX phosphorylation, MDMX–14-3-3 binding, and p53 activation were drastically reduced in mouse embryo fibroblasts harboring endogenous MDMX with S341A (mouse homologue of human serine 342), S367A, and S402A (mouse homologue of human serine 403) mutations. Moreover, deficiency of AMPK prevented MDMX–14-3-3 interaction and p53 activation. The activation of p53 through AMPK-mediated MDMX phosphorylation and inactivation was further confirmed by using cell and animal model systems with two AMPK activators, metformin and salicylate (the active form of aspirin). Together, the results unveil a mechanism by which metabolic stresses activate AMPK, which, in turn, phosphorylates and inactivates MDMX, resulting in p53 stabilization and activation.
    Keywords AMP-activated protein kinase ; animal models ; aspirin ; fibroblasts ; humans ; metformin ; mice ; phosphorylation ; serine
    Language English
    Dates of publication 2014-0101
    Size p. 148-157.
    Publishing place Taylor & Francis
    Document type Article ; Online
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00670-13
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  4. Article ; Online: Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases.

    Wang, Yunyuan V / Leblanc, Mathias / Wade, Mark / Jochemsen, Aart G / Wahl, Geoffrey M

    Cancer cell

    2009  Volume 16, Issue 1, Page(s) 33–43

    Abstract: Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Posttranslational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this ... ...

    Abstract Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Posttranslational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this model in vivo, where critical stoichiometric relationships are preserved. We generated an Mdmx mutant mouse in which three conserved serines (S341, S367, S402) targeted by DNA-damage-activated kinases were replaced by alanines to investigate whether modifications of these residues are important for Mdmx degradation and p53 activation. The mutant mice were remarkably resistant to radiation, and very susceptible to Myc-induced lymphomagenesis. These data demonstrate that Mdmx downregulation is crucial for effective p53-mediated radiation responses and tumor suppression in vivo.
    MeSH term(s) Animals ; Blotting, Southern ; Codon/genetics ; Conserved Sequence ; DNA Damage/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease/genetics ; Genotype ; Homozygote ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/radiotherapy ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Polymerase Chain Reaction ; Proto-Oncogene Proteins c-mdm2/genetics ; Recombination, Genetic ; Serine ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Codon ; Tumor Suppressor Protein p53 ; Serine (452VLY9402) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2009-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccr.2009.05.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Hypoxia activates tumor suppressor p53 by inducing ATR-Chk1 kinase cascade-mediated phosphorylation and consequent 14-3-3γ inactivation of MDMX protein.

    Lee, Jun-Ho / Jin, Yetao / He, Guifen / Zeng, Shelya X / Wang, Yunyuan V / Wahl, Geoffrey M / Lu, Hua

    The Journal of biological chemistry

    2012  Volume 287, Issue 25, Page(s) 20898–20903

    Abstract: It has been known that p53 can be induced and activated by hypoxia, an abnormal condition that often occurs in rapidly growing solid tumors or when normal tissues undergo ischemia. Although the ATR-Chk1 kinase cascade was associated with hypoxia-induced ... ...

    Abstract It has been known that p53 can be induced and activated by hypoxia, an abnormal condition that often occurs in rapidly growing solid tumors or when normal tissues undergo ischemia. Although the ATR-Chk1 kinase cascade was associated with hypoxia-induced p53 activation, molecules that directly link this hypoxia-ATR-Chk1 pathway to p53 activation have been elusive. Here, we showed that hypoxia could induce phosphorylation of MDMX at Ser-367 and enhance the binding of this phosphorylated MDMX to 14-3-3γ, consequently leading to p53 activation. A Chk1 inhibitor or knockdown of ATR and Chk1 inhibited the phosphorylation of MDMX at Ser-367 and impaired the binding of MDMX to 14-3-3γ in addition to p53 activation in response to hypoxia. In primary mouse embryonic fibroblast cells that harbor a mutant MDMX, including the S367A mutation, hypoxia also failed to induce the binding of this mutant MDMX to 14-3-3γ and to activate p53 and its direct targets. These results demonstrate that hypoxia can activate p53 through inactivation of MDMX by the ATR-Chk1-MDMX-14-3-3γ pathway.
    MeSH term(s) 14-3-3 Proteins/genetics ; 14-3-3 Proteins/metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Hypoxia/physiology ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Embryo, Mammalian/cytology ; Embryo, Mammalian/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Mice ; Mutation ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation/physiology ; Protein Binding/physiology ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances 14-3-3 Proteins ; Cell Cycle Proteins ; MDM4 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Protein Kinases (EC 2.7.-) ; Atr protein, mouse (EC 2.7.1.-) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Chek1 protein, mouse (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2012-05-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M111.336875
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation.

    Wang, Yunyuan V / Wade, Mark / Wong, Eetsin / Li, Yao-Cheng / Rodewald, Luo Wei / Wahl, Geoffrey M

    Proceedings of the National Academy of Sciences of the United States of America

    2007  Volume 104, Issue 30, Page(s) 12365–12370

    Abstract: P53 regulates numerous downstream targets to induce cell cycle arrest, senescence, apoptosis, and DNA repair in response to diverse stresses. Hdm2 and Hdmx are critical negative regulators of P53 because Hdm2 regulates P53 abundance, and both can ... ...

    Abstract P53 regulates numerous downstream targets to induce cell cycle arrest, senescence, apoptosis, and DNA repair in response to diverse stresses. Hdm2 and Hdmx are critical negative regulators of P53 because Hdm2 regulates P53 abundance, and both can antagonize P53 transactivation. Modest changes in Hdm2 or Hdmx abundance affect P53 regulation, yet quantitative information regarding their endogenous intracellular concentrations and subcellular distributions during a stress response are lacking. We analyzed these parameters in normal and cancer cells after DNA damage. Our data show that the nuclear abundance of Hdm2 and Hdmx relative to P53 limits P53 activity in cells growing in culture. Upon DNA damage, P53 nuclear abundance increases, whereas Hdm2 and Hdmx stability decreases, which greatly limits their ability to antagonize P53, regardless of their levels. These data indicate that the damage-activated switch in Hdm2 ubiquitin ligase preference from P53 to itself and Hdmx is central to P53 activation.
    MeSH term(s) Cell Line ; DNA/genetics ; DNA Damage/genetics ; Gene Expression Regulation ; Humans ; Kinetics ; Nuclear Proteins/analysis ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Binding ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Transcriptional Activation/genetics ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances MDM4 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; Tumor Suppressor Protein p53 ; DNA (9007-49-2)
    Language English
    Publishing date 2007-07-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0701497104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity.

    He, Guifen / Zhang, Yi-Wei / Lee, Jun-Ho / Zeng, Shelya X / Wang, Yunyuan V / Luo, Zhijun / Dong, X Charlie / Viollet, Benoit / Wahl, Geoffrey M / Lu, Hua

    Molecular and cellular biology

    2013  Volume 34, Issue 2, Page(s) 148–157

    Abstract: AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in ... ...

    Abstract AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in vitro and in cells, leading to enhanced association between MDMX and 14-3-3. This markedly inhibits p53 ubiquitylation and significantly stabilizes and activates p53. By striking contrast, no phosphorylation of MDM2 by AMPK was noted. AMPK-mediated MDMX phosphorylation, MDMX-14-3-3 binding, and p53 activation were drastically reduced in mouse embryo fibroblasts harboring endogenous MDMX with S341A (mouse homologue of human serine 342), S367A, and S402A (mouse homologue of human serine 403) mutations. Moreover, deficiency of AMPK prevented MDMX-14-3-3 interaction and p53 activation. The activation of p53 through AMPK-mediated MDMX phosphorylation and inactivation was further confirmed by using cell and animal model systems with two AMPK activators, metformin and salicylate (the active form of aspirin). Together, the results unveil a mechanism by which metabolic stresses activate AMPK, which, in turn, phosphorylates and inactivates MDMX, resulting in p53 stabilization and activation.
    MeSH term(s) 14-3-3 Proteins/metabolism ; Adenylate Kinase/metabolism ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cell Cycle Checkpoints ; Cell Cycle Proteins ; Gene Knockout Techniques ; HCT116 Cells ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Sequence Data ; Nuclear Proteins/chemistry ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Binding ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Stress, Physiological ; Tumor Suppressor Protein p53/metabolism ; Ubiquitination
    Chemical Substances 14-3-3 Proteins ; Cell Cycle Proteins ; MDM4 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Adenylate Kinase (EC 2.7.4.3)
    Language English
    Publishing date 2013-11-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00670-13
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Linking the p53 tumour suppressor pathway to somatic cell reprogramming.

    Kawamura, Teruhisa / Suzuki, Jotaro / Wang, Yunyuan V / Menendez, Sergio / Morera, Laura Batlle / Raya, Angel / Wahl, Geoffrey M / Izpisúa Belmonte, Juan Carlos

    Nature

    2009  Volume 460, Issue 7259, Page(s) 1140–1144

    Abstract: Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this ... ...

    Abstract Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.
    MeSH term(s) Animals ; Cells, Cultured ; Cellular Reprogramming/physiology ; Cyclin-Dependent Kinase Inhibitor p21/deficiency ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Down-Regulation ; Embryo, Mammalian/cytology ; Female ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Humans ; Keratinocytes ; Male ; Mice ; Mice, Inbred C57BL ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/metabolism ; Tumor Suppressor Protein p53/deficiency ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Cyclin-Dependent Kinase Inhibitor p21 ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2009-08-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature08311
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Quantitative analyses reveal the importance of regulated Hdmx degradation for P53 activation

    Wang, Yunyuan V / Wade, Mark / Wong, EeTsin / Li, Yao-Cheng / Rodewald, Luo Wei / Wahl, Geoffrey M

    Proceedings of the National Academy of Sciences of the United States of America. 2007 July 24, v. 104, no. 30

    2007  

    Abstract: P53 regulates numerous downstream targets to induce cell cycle arrest, senescence, apoptosis, and DNA repair in response to diverse stresses. Hdm2 and Hdmx are critical negative regulators of P53 because Hdm2 regulates P53 abundance, and both can ... ...

    Abstract P53 regulates numerous downstream targets to induce cell cycle arrest, senescence, apoptosis, and DNA repair in response to diverse stresses. Hdm2 and Hdmx are critical negative regulators of P53 because Hdm2 regulates P53 abundance, and both can antagonize P53 transactivation. Modest changes in Hdm2 or Hdmx abundance affect P53 regulation, yet quantitative information regarding their endogenous intracellular concentrations and subcellular distributions during a stress response are lacking. We analyzed these parameters in normal and cancer cells after DNA damage. Our data show that the nuclear abundance of Hdm2 and Hdmx relative to P53 limits P53 activity in cells growing in culture. Upon DNA damage, P53 nuclear abundance increases, whereas Hdm2 and Hdmx stability decreases, which greatly limits their ability to antagonize P53, regardless of their levels. These data indicate that the damage-activated switch in Hdm2 ubiquitin ligase preference from P53 to itself and Hdmx is central to P53 activation.
    Language English
    Dates of publication 2007-0724
    Size p. 12365-12370.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    Database NAL-Catalogue (AGRICOLA)

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  10. Article ; Online: Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.

    Wang, Yunyuan V / Leblanc, Mathias / Fox, Norma / Mao, Jian-Hua / Tinkum, Kelsey L / Krummel, Kurt / Engle, Dannielle / Piwnica-Worms, David / Piwnica-Worms, Helen / Balmain, Allan / Kaushansky, Kenneth / Wahl, Geoffrey M

    Genes & development

    2011  Volume 25, Issue 13, Page(s) 1426–1438

    Abstract: Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC ... ...

    Abstract Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.
    MeSH term(s) Animals ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Female ; Gamma Rays ; Gene Dosage ; Gene Expression Regulation ; Gene Knock-In Techniques ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/radiation effects ; Homeostasis/genetics ; Longevity/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mutation ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Radiation Tolerance/genetics ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Cyclin-Dependent Kinase Inhibitor p21 ; Tumor Suppressor Protein p53 ; Mdm2 protein, mouse (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2011-07-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.2024411
    Database MEDical Literature Analysis and Retrieval System OnLINE

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