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1.
Stem Cell Reports ; 13(3): 559-571, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31402338

RESUMO

Development of spermatogonia and spermatocytes are the critical steps of spermatogenesis, impacting on male fertility. Investigation of the related regulators benefits the understanding of male reproduction. The proteasome system has been reported to regulate spermatogenesis, but the mechanisms and key contributing factors in vivo are poorly explored. Here we found that ablation of REGγ, a proteasome activator, resulted in male subfertility. Analysis of the mouse testes after birth showed there was a decreased number of PLZF+ spermatogonia and spermatocytes. Molecular analysis found that REGγ loss significantly increased the abundance of p53 protein in the testis, and directly repressed PLZF transcription in cell lines. Of note, allelic p53 haplodeficiency partially rescued the defects in spermatogenesis observed in REGγ-deficient mice. In summary, our results identify REGγ-p53-PLZF to be a critical pathway that regulates spermatogenesis and establishes a new molecular link between the proteasome system and male reproduction.


Assuntos
Autoantígenos/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Espermatogênese , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Autoantígenos/genética , Masculino , Meiose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oligonucleotídeos Antissenso , Regiões Promotoras Genéticas , Proteína com Dedos de Zinco da Leucemia Promielocítica/antagonistas & inibidores , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica , Transdução de Sinais , Motilidade dos Espermatozoides , Espermatócitos/citologia , Espermatócitos/metabolismo , Espermatogônias/citologia , Espermatogônias/metabolismo , Testículo/metabolismo , Proteína Supressora de Tumor p53/genética
2.
Proc Natl Acad Sci U S A ; 110(27): 11005-10, 2013 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-23766372

RESUMO

Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ(-/-) MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.


Assuntos
Senilidade Prematura/etiologia , Senilidade Prematura/metabolismo , Caseína Quinase Idelta/metabolismo , Complexo de Endopeptidases do Proteassoma/deficiência , Senilidade Prematura/patologia , Animais , Autoantígenos/genética , Feminino , Genes p53 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pele/metabolismo , Pele/patologia , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
J Cell Sci ; 123(Pt 23): 4076-84, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21084564

RESUMO

The proteasome activator REGγ mediates a shortcut for the destruction of intact mammalian proteins. The biological roles of REGγ and the underlying mechanisms are not fully understood. Here we provide evidence that REGγ regulates cellular distribution of p53 by facilitating its multiple monoubiquitylation and subsequent nuclear export and degradation. We also show that inhibition of p53 tetramerization by REGγ might further enhance cytoplasmic relocation of p53 and reduce active p53 in the nucleus. Furthermore, multiple monoubiquitylation of p53 enhances its physical interaction with HDM2 and probably facilitates subsequent polyubiquitylation of p53, suggesting that monoubiquitylation can act as a signal for p53 degradation. Depletion of REGγ sensitizes cells to stress-induced apoptosis, validating its crucial role in the control of apoptosis, probably through regulation of p53 function. Using a mouse xenograft model, we show that REGγ knockdown results in a significant reduction of tumor growth, suggesting an important role for REGγ in tumor development. Our study therefore demonstrates that REGγ-mediated inactivation of p53 is one of the mechanisms involved in cancer progression.


Assuntos
Autoantígenos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Autoantígenos/genética , Linhagem Celular Tumoral , Núcleo Celular/química , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/química , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica , Multimerização Proteica , Transporte Proteico , Distribuição Aleatória , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Ubiquitinação
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