RESUMO
The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme complex that regulates many fundamental cellular processes. PP2A is involved in tumorigenesis because mutations in the scaffold subunit, PPP2R1B, were found in several types of cancers. However, the biological function of PPP2R1B remains largely unknown. We report here that homozygous deletion of Ppp2r1b in Mus musculus impairs meiotic recombination and causes meiotic arrest in spermatocytes. Consistently, male mice lacking Ppp2r1b are characterized with infertility. Furthermore, heterozygous missense mutations in the Homo sapiens PPP2R1B gene, which encodes PPP2R1B, are identified in azoospermia patients with meiotic arrest. We found that PPP2R1B mutants are susceptible to degradation by an E3 ligase CRL4ADCAF6 , and resistant to de-polyubiquitylation by ubiquitin-specific protease 5 (USP5). In addition, heterozygous mutations in PPP2R1B reduce stability of the wild-type PPP2R1B. Our results demonstrate an essential role of PPP2R1B in spermatogenesis and identify upstream regulators of PPP2R1B.
Assuntos
Infertilidade Masculina/patologia , Mutação , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/fisiologia , Espermatogênese , Testículo/patologia , Ubiquitinação , Animais , Família , Feminino , Homozigoto , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Masculino , Meiose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Fosfatase 2/genética , Testículo/metabolismoRESUMO
Eg5 is a kinesin spindle protein that controls chromosomal segregation in mitosis and is thus a critical drug target for cancer therapy. We report the discovery of a potent, selective inhibitor of Eg5 designated YL001. YL001 was obtained through shape similarity based virtual screening, and it bears a 1,5-disubstituted tetrazole scaffold. YL001 exhibits favorable bioactivity in a variety of cancer cell lines, including taxol-resistant ovarian cancer and 6TG-resistant breast cancer cell lines. This compound inhibits tumor growth by 60% and significantly prolongs median survival time by more than 50% in a xenograft mouse model. YL001 blocks the ATPase activity of Eg5 and causes mitotic failure, ultimately resulting in apoptosis of cancer cells through activation of the caspase-3 pathway. Our findings demonstrate that YL001 is a potent antitumor agent that may be developed for cancer therapeutics.
