5-alpha-reductase

2012年12月1日星期六

Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts.

Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts.

Mol Biol Cell. 2005 Mar;16(3):1305-18

Authors: Gadea BB, Ruderman JV

Abstract
The Aurora family kinases contribute to accurate progression through several mitotic events. ZM447439 ("ZM"), the first Aurora family kinase inhibitor to be developed and characterized, was previously found to interfere with the mitotic spindle integrity checkpoint and chromosome segregation. Here, we have used extracts of Xenopus eggs, which normally proceed through the early embryonic cell cycles in the absence of functional checkpoints, to distinguish between ZM's effects on the basic cell cycle machinery and its effects on checkpoints. ZM clearly had no effect on either the kinetics or amplitude in the oscillations of activity of several key cell cycle regulators. It did, however, have striking effects on chromosome morphology. In the presence of ZM, chromosome condensation began on schedule but then failed to progress properly; instead, the chromosomes underwent premature decondensation during mid-mitosis. ZM strongly interfered with mitotic spindle assembly by inhibiting the formation of microtubules that are nucleated/stabilized by chromatin. By contrast, ZM had little effect on the assembly of microtubules by centrosomes at the spindle poles. Finally, under conditions where the spindle integrity checkpoint was experimentally induced, ZM blocked the establishment, but not the maintenance, of the checkpoint, at a point upstream of the checkpoint protein Mad2. These results show that Aurora kinase activity is required to ensure the maintenance of condensed chromosomes, the generation of chromosome-induced spindle microtubules, and activation of the spindle integrity checkpoint.

PMID: 15616188 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Regulation of the meiotic prophase I to metaphase I transition in mouse spermatocytes.

Regulation of the meiotic prophase I to metaphase I transition in mouse spermatocytes.

Chromosoma. 2008 Oct;117(5):471-85

Authors: Sun F, Handel MA

Abstract
The meiotic prophase I to metaphase I transition (G2/MI) involves disassembly of synaptonemal complex (SC), chromatin condensation, and final compaction of morphologically distinct MI bivalent chromosomes. Control of these processes is poorly understood. The G2/MI transition was experimentally induced in mouse pachytene spermatocytes by okadaic acid (OA), and kinetic analysis revealed that disassembly of the central element of the SC occurred very rapidly after OA treatment, before histone H3 phosphorylation on Ser10. These events were followed by relocalization of SYCP3 and final condensation of bivalents. Enzymatic control of these G2/MI transition events was studied using small molecule inhibitors: butyrolactone I (BLI), an inhibitor of cyclin-dependent kinases (CDKs) and ZM447439 (ZM), an inhibitor of aurora kinases (AURKs). The formation of highly condensed MI bivalents and disassembly of the SC are regulated by both CDKs and AURKs. AURKs also mediate phosphorylation of histone H3 in meiosis. However, neither BLI nor ZM inhibited disassembly of the central element of the SC. Thus, despite evidence that the metaphase promoting factor is a universal regulator of the onset of cell division, desynapsis, the first and key step of the G2/MI transition, occurs independently of BLI-sensitive CDKs and ZM-sensitive AURKs.

PMID: 18563426 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Histone post-translational modification: from discovery to the clinic.

Histone post-translational modification: from discovery to the clinic.

IDrugs. 2006 Jun;9(6):398-401

Authors: Thomas NR

PMID: 16752306 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Aurora kinase B modulates chromosome alignment in mouse oocytes.

Aurora kinase B modulates chromosome alignment in mouse oocytes.

Mol Reprod Dev. 2009 Nov;76(11):1094-105

Authors: Shuda K, Schindler K, Ma J, Schultz RM, Donovan PJ

Abstract
The elevated incidence of aneuploidy in human oocytes warrants study of the molecular mechanisms regulating proper chromosome segregation. The Aurora kinases are a well-conserved family of serine/threonine kinases that are involved in proper chromosome segregation during mitosis and meiosis. Here we report the expression and localization of all three Aurora kinase homologs, AURKA, AURKB, and AURKC, during meiotic maturation of mouse oocytes. AURKA, the most abundantly expressed homolog, localizes to the spindle poles during meiosis I (MI) and meiosis II (MII), whereas AURKB is concentrated at kinetochores, specifically at metaphase of MI (Met I). The germ cell-specific homolog, AURKC, is found along the entire length of chromosomes during both meiotic divisions. Maturing oocytes in the presence of the small molecule pan-Aurora kinase inhibitor, ZM447439 results in defects in meiotic progression and chromosome alignment at both Met I and Met II. Over-expression of AURKB, but not AURKA or AURKC, rescues the chromosome alignment defect suggesting that AURKB is the primary Aurora kinase responsible for regulating chromosome dynamics during meiosis in mouse oocytes.

PMID: 19565641 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Exp Cell Res. 2009 Apr 15;315(7):1085-99

Authors: Dreier MR, Grabovich AZ, Katusin JD, Taylor WR

Abstract
Aurora kinases are essential for mitosis and are candidate targets of novel chemotherapeutic agents. The inhibitors ZM447439, MK-0457 (VX-680) as well as Hesperadin have been used to dissect the roles of Aurora kinases in the cell cycle and have been tested clinically for the treatment of cancer. Here we have carried out a detailed kinetic analysis of two isogenic cell lines differing in p53 function and have compared the effects of ZM447439 and VE-465 (related to MK-0457). We find that p53 is needed for efficient cell cycle arrest when Aurora kinases are inhibited by either ZM447439 or VE-465. However, the p53-induced cell cycle block is neither immediate nor absolute. ZM447439 induced the localized accumulation of gammaH2A.X indicating that p53 induction by this drug occurs in response to DNA damage. Our analysis of the long-term effects of ZM447439 indicates that cells can evade killing by the drug, but not via a classical drug-resistance mechanism. Several mechanisms to explain how cells may evade killing by Aurora kinase inhibitors are described.

PMID: 19233169 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

2012年11月30日星期五

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Exp Cell Res. 2009 Apr 15;315(7):1085-99

Authors: Dreier MR, Grabovich AZ, Katusin JD, Taylor WR

PMID: 19233169 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.

Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.

Cell Cycle. 2008 Oct;7(20):3187-93

Authors: Ganguly A, Bhattacharya R, Cabral F

Abstract
MCAK, a kinesin related motor protein with microtubule depolymerizing activity, is known to play an important role in spindle assembly and correcting errors in mitotic chromosome alignment. Experiments to determine how cellular levels of the protein are regulated demonstrate that MCAK accumulates during cell cycle progression, reaches a maximum at G(2)/M phase, and is rapidly degraded by the proteasome during mitosis. Immunofluorescence microscopy further indicates that MCAK largely disappears from kinetochores and spindle poles at the metaphase to anaphase transition. A phosphorylated form of MCAK appears during mitosis and seems to be preferentially degraded, but degradation does not appear to depend on Aurora B, a kinase reported to be involved in regulating the error correcting activity of the protein. These studies indicate that MCAK activity is limited during the latter stages of mitosis by protein degradation, and argue against a role for the protein in anaphase chromosome movement.

PMID: 18843200 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

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