RESUMO
Polo-like kinase 1 (Plk1) is instrumental for mitotic entry and progression. Plk1 is activated by phosphorylation on a conserved residue Thr210 in its activation segment by the Aurora A kinase (AURKA), a reaction that critically requires the co-factor Bora phosphorylated by a CyclinA/B-Cdk1 kinase. Here we show that phospho-Bora is a direct activator of AURKA kinase activity. We localize the key determinants of phospho-Bora function to a 100 amino acid region encompassing two short Tpx2-like motifs and a phosphoSerine-Proline motif at Serine 112, through which Bora binds AURKA. The latter substitutes in trans for the Thr288 phospho-regulatory site of AURKA, which is essential for an active conformation of the kinase domain. We demonstrate the importance of these determinants for Bora function in mitotic entry both in Xenopus egg extracts and in human cells. Our findings unveil the activation mechanism of AURKA that is critical for mitotic entry.
Assuntos
Aurora Quinase A/metabolismo , Proteínas de Ciclo Celular/metabolismo , Mitose , Treonina/metabolismo , Motivos de Aminoácidos/genética , Animais , Aurora Quinase A/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Ciclina A2/genética , Ciclina A2/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Ativação Enzimática , Feminino , Humanos , Oócitos/metabolismo , Fosforilação , Prolina/genética , Prolina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Serina/genética , Serina/metabolismo , Treonina/genética , Xenopus laevis , Quinase 1 Polo-LikeRESUMO
A fundamental question in developmental biology is how different cell lineages acquire different cell cycle durations. With its highly stereotypical asymmetric and asynchronous cell divisions, the early Caenorhabditis elegans embryo provides an ideal system to study lineage-specific cell cycle timing regulation during development, with high spatio-temporal resolution. The first embryonic division is asymmetric and generates two blastomeres of different sizes (AB>P1) and developmental potentials that divide asynchronously, with the anterior somatic blastomere AB dividing reproducibly two minutes before the posterior germline blastomere P1. The evolutionarily conserved PAR proteins (abnormal embryonic PARtitioning of cytoplasm) regulate all of the asymmetries in the early embryo including cell cycle asynchrony between AB and P1 blastomeres. Here we discuss our current understanding and open questions on the mechanism by which the PAR proteins regulate asynchronous cell divisions in the early C. elegans embryo.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/embriologia , Pontos de Checagem do Ciclo Celular/fisiologia , Ciclo Celular/fisiologia , Embrião não Mamífero/citologia , Animais , Caenorhabditis elegans/fisiologia , Divisão Celular , Embrião não Mamífero/metabolismoRESUMO
BACKGROUND: Inflammatory bowel diseases (IBD) typically affect young patients during the reproductive years, and reproductive issues are of key concern to them. AIM: To evaluate the impact of IBD on fertility in both women and men with IBD who had no history of surgical treatment for IBD. METHODS: We searched MEDLINE, Cochrane Library, EMBASE and international conference abstracts and included all controlled observational studies that evaluated fertility in Crohn's disease (CD) and/or ulcerative colitis (UC) in women and/or men. RESULTS: Eleven studies matching our criteria were included. In women with CD, there was a 17-44% reduction in fertility as compared with controls. Reduction in fertility was linked to voluntary childlessness, while there was no evidence of physiological causes of infertility. Most studies did not find any reduction in fertility in women with UC as compared with controls. In men with CD, there was an 18-50% reduction in fertility as compared with controls with no difference in reproductive capacity. There was no evidence of reduced fertility in men with UC. CONCLUSIONS: The infertility observed in both women and men with CD is due to voluntary childlessness as opposed to involuntary infertility. This voluntary childlessness is often based on incorrect beliefs about the impact of the disease on fertility and pregnancy outcomes. Our results reinforce the need to increase awareness among male and female patients that IBD does not itself lead to reduced fertility.
