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1.
Proc Natl Acad Sci U S A ; 114(40): 10660-10665, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28923932

RESUMO

MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.


Assuntos
Proteínas de Ciclo Celular/biossíntese , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , MicroRNAs/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular , Cílios/genética , Cílios/metabolismo , Tubas Uterinas/citologia , Tubas Uterinas/metabolismo , Feminino , Camundongos , MicroRNAs/genética , Células-Tronco Embrionárias Murinas/citologia , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo
2.
Nat Cell Biol ; 16(11): 1080-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25344755

RESUMO

Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.


Assuntos
Ciclina C/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/metabolismo , Animais , Células Cultivadas , Quinase 3 Dependente de Ciclina/metabolismo , Quinase 8 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/genética , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
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