JAMES MALLER

..CSF arrest in vertebrate oocytes by p90Rsk provides a potential link between the MAPK pathway and the spindle assembly checkpoint in the cell cycle...

..Collectively, our data demonstrate a key role for Rsk1 in the differentiation process of PC12 cells...

..CSF arrest in vertebrate oocytes by p90(Rsk) provides a link between the MAPK pathway and the spindle assembly checkpoint in the cell cycle...

..Taken together, these results indicate that the polo box is required for Plx1 function in both the G(2)-M and the metaphase/anaphase transitions during the cell cycle...

..These results suggest a model in which CSF arrest by Mos is mediated by the Mad1 and Mad2 proteins in a manner distinct from the spindle checkpoint...

..The identification of substrates for PKAc that maintain cell cycle arrest in G(2) remains an important goal for future work...

..However, connections between the Plx1 pathway and the CaMKII pathway have not been identified...

..These results indicate that xPlkk1 may function downstream as a target of Plx1 rather than as an upstream activating kinase during the G(2)/M transition...

..These results uniquely place xMps1 downstream of cyclin E-Cdk2 in mediating a pathway of APC/C inhibition and metaphase arrest...

..Both pathways are independent of each other, but each appears to block activation of the APC, which is required for cyclin B degradation and the metaphase/anaphase transition...

..However, depletion of the protein from cycling egg extracts does not prevent mitotic cell cycle progression. Thus, Emi2 plays an essential role in meiotic but not mitotic cell cycles...

..These results suggest that XmPRbeta is a physiological progesterone receptor involved in initiating the resumption of meiosis during maturation of Xenopus oocytes...

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..These results indicate that the cyclin A CLS may contribute to targeting and recognition of centrosomal Cdk substrates and is required for specific effects of p27(KIP1) on cyclin A-Cdk2...

..Prevention of the decrease in Aurora B activity at fertilization by expression of ectopic wild-type INCENP, but not kinase-dead Aurora B INCENP, blocked calcium-induced exit from metaphase arrest in egg extracts...

..Importantly, injection of Eg5 into TPX2-CT-arrested blastomeres causes resumption of cleavage. These results define a discrete domain within the C terminus of TPX2 that exerts a novel Eg5-dependent function in spindle pole segregation...

..These results indicate that calcium, calmodulin, and CaMKII are required for an essential step in initiation of centrosome duplication. Our data suggest that calcium oscillations in the cell cycle may be linked to centrosome duplication...

..Our studies suggest that targeting of TPX2 might be an effective strategy for specifically inhibiting the phosphorylation of Aurora A substrates, including p53...

..Interestingly, inhibition is blocked by TPX2, suggesting that the ability of Aurora A to transform cells could be regulated by p53, TPX2, or other binding proteins...

..These data suggest that caspase cleavage of both cyclin D1-Cdk4 and cyclin A2-Cdk2 promotes specific apoptotic events in embryos undergoing apoptosis in response to ionizing radiation...

..Taken together, our data indicate that Plx1 promotes activation of Aurora A, most likely through TPX2. In light of the current literature, we propose a model in which Plx1 and Aurora A activate each other in a positive feedback loop...

..During mitosis, Plk1-dependent Bora degradation promotes Aurora A localization to the centrosome and/or spindle. Bora-dependent regulation provides important new insights into interactions between key mitotic kinases...

..We propose that this novel mode of "in trans" regulation is employed in the DNA damage response to modulate a broad range of chromatin-associated activities in a genome-wide manner...

..The generation of an activated mutant of Aurora B will be important for studying its role in cell cycle control and tumorigenesis...

..Plx1 is also required for cytokinesis and is localized on the midbody of the contractile ring. All known functions of Plx1 require not only its kinase activity but also an intact polo box domain in the C-terminus...

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..Checkpoint activation induced by DNA double-strand breaks (DSB) is dependent on the ATM kinase, a master regulator of the DNA damage response (DDR) that is activated through autophosphorylation and monomerization...

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..Moreover, we demonstrate a significant difference in enrichment of phosphopeptides when different resins are used for Fe3+-IMAC and characterize the strengths and limitations of this methodology for the study of phosphoproteomics...

..Experiments will evaluate whether Bub1 mediates CSF arrest by the MAPK pathway. This work provides a link between the MAPK/Rsk pathway and checkpoint control of the cell cycle at the metaphase/anaphase transition. ..

..Such altered phosphoproteins may be candidates for regulatory molecules that maintain the physiological arrest of the oocyte on prophase...

..The network between MPF and proto-oncogenes like c-src provides a novel basis for investigating the interface between cell cycle control and cell growth control...

..Further work will examine the regulation, localization, and targets of PIx1 and identify kinases that activate xPIkk1. ..

..Aim 2 proposes to investigate the mechanism of activation of Rsk by multi-site phosphorylation mediated by multiple kinases. Aim 3 proposes to determine the mechanisms of inhibition of MAP kinase activation by cAMP. ..

..The work proposed in this grant should help elucidate the molecular control of the cell cycle at the G2/M transition in normal cells, providing a framework for comparison with the controls in cancer cells. ..

..By examining both S6 kinases and phosphatases, the complete regulation of this pathway of signal transduction will be evaluated...

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