Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells.

• Klíčová slova
• ATM, ATR, Chk1, DNA damage response, Wee1, cancer, checkpoint, inhibitor, p53, replication stress,
• MeSH
• buněčná smrt účinky léků   MeSH
• cílená molekulární terapie metody   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory farmakoterapie   enzymologie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• nádorový supresorový protein p53 MeSH

Polo-like kinase 1 (PLK1) orchestrates multiple events of cell division. Although PLK1 function has been intensively studied in centriole-containing and rapidly cycling somatic cells, much less is known about its function in the meiotic divisions of mammalian oocytes, which arrest for a long period of time in prophase before meiotic resumption and lack centrioles for spindle assembly. Here, using specific small molecule inhibition combined with live mouse oocyte imaging, we comprehensively characterize meiotic PLK1's functions. We show that PLK1 becomes activated at meiotic resumption on microtubule organizing centers (MTOCs) and later at kinetochores. PLK1 is required for efficient meiotic resumption by promoting nuclear envelope breakdown. PLK1 is also needed to recruit centrosomal proteins to acentriolar MTOCs to promote normal spindle formation, as well as for stable kinetochore-microtubule attachment. Consequently, PLK1 inhibition leads to metaphase I arrest with misaligned chromosomes activating the spindle assembly checkpoint (SAC). Unlike in mitosis, the metaphase I arrest is not bypassed by the inactivation of the SAC. We show that PLK1 is required for the full activation of the anaphase promoting complex/cyclosome (APC/C) by promoting the degradation of the APC/C inhibitor EMI1 and is therefore essential for entry into anaphase I. Moreover, our data suggest that PLK1 is required for proper chromosome segregation and the maintenance of chromosome condensation during the meiosis I-II transition, independently of the APC/C. Thus, our results define the meiotic roles of PLK1 in oocytes and reveal interesting differential requirements of PLK1 between mitosis and oocyte meiosis in mammals.

• MeSH
• anafázi podporující komplex metabolismus   MeSH
• jaderný obal metabolismus   MeSH
• kinetochory metabolismus   MeSH
• konfokální mikroskopie MeSH
• meióza fyziologie   MeSH
• myši MeSH
• oocyty růst a vývoj   MeSH
• organizační centrum mikrotubulů metabolismus   MeSH
• počítačové zpracování obrazu MeSH
• polo-like kinasa 1 MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• protoonkogenní proteiny metabolismus   MeSH
• segregace chromozomů fyziologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anafázi podporující komplex MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny MeSH