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Douglas R Kellogg - One of the best experts on this subject based on the ideXlab platform.
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the zds proteins control entry into mitosis and target protein phosphatase 2a to the cdc25 phosphatase
Molecular Biology of the Cell, 2011Co-Authors: Sidonie Wicky, John R Yates, Hendri Tjandra, David Schieltz, Douglas R KelloggAbstract:The Wee1 Kinase restrains entry into mitosis by phosphorylating and inhibiting Cyclin-Dependent Kinase 1 (Cdk1). The Cdc25 phosphatase promotes entry into mitosis by removing Cdk1 inhibitory phosphorylation. Experiments in diverse systems have established that Wee1 and Cdc25 are regulated by protein phosphatase 2A (PP2A), but a full understanding of the function and regulation of PP2A in entry into mitosis has remained elusive. In budding yeast, entry into mitosis is controlled by a specific form of PP2A that is associated with the Cdc55 regulatory subunit (PP2ACdc55). We show here that related proteins called Zds1 and Zds2 form a tight stoichiometric complex with PP2ACdc55 and target its activity to Cdc25 but not to Wee1. Conditional inactivation of the Zds proteins revealed that their function is required primarily at entry into mitosis. In addition, Zds1 undergoes cell cycle–dependent changes in phosphorylation. Together, these observations define a role for the Zds proteins in controlling specific functions of PP2ACdc55 and suggest that upstream signals that regulate PP2ACdc55 may play an important role in controlling entry into mitosis.
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regulation of mih1 cdc25 by protein phosphatase 2a and casein Kinase 1
Journal of Cell Biology, 2008Co-Authors: Maria T Z Paraz, Douglas R KelloggAbstract:The Cdc25 phosphatase promotes entry into mitosis by removing Cyclin-Dependent Kinase 1 (Cdk1) inhibitory phosphorylation. Previous work suggested that Cdc25 is activated by Cdk1 in a positive feedback loop promoting entry into mitosis; however, it has remained unclear how the feedback loop is initiated. To learn more about the mechanisms that regulate entry into mitosis, we have characterized the function and regulation of Mih1, the budding yeast homologue of Cdc25. We found that Mih1 is hyperphosphorylated early in the cell cycle and is dephosphorylated as cells enter mitosis. Casein Kinase 1 is responsible for most of the hyperphosphorylation of Mih1, whereas protein phosphatase 2A associated with Cdc55 dephosphorylates Mih1. Cdk1 appears to directly phosphorylate Mih1 and is required for initiation of Mih1 dephosphorylation as cells enter mitosis. Collectively, these observations suggest that Mih1 regulation is achieved by a balance of opposing Kinase and phosphatase activities. Because casein Kinase 1 is associated with sites of polar growth, it may regulate Mih1 as part of a signaling mechanism that links successful completion of growth-related events to cell cycle progression.
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cdk1 dependent regulation of the mitotic inhibitor wee1
Cell, 2005Co-Authors: Stacy L Harvey, Alyson Charlet, Wilhelm Haas, Stephen P. Gygi, Douglas R KelloggAbstract:The Wee1 Kinase phosphorylates and inhibits Cyclin-Dependent Kinase 1 (Cdk1), thereby delaying entry into mitosis until appropriate conditions have been met. An understanding of the mechanisms that regulate Wee1 should provide new insight into how cells make the decision to enter mitosis. We report here that Swe1, the budding-yeast homolog of Wee1, is directly regulated by Cdk1. Phosphorylation of Swe1 by Cdk1 activates Swe1 and is required for formation of a stable Swe1-Cdk1 complex that maintains Cdk1 in the inhibited state. Dephosphorylation of Cdk1 leads to further phosphorylation of Swe1 and release of Cdk1. Thus, Cdk1 both positively and negatively regulates its own inhibitor. Regulation of the Swe1-Cdk1 complex is likely to play a critical role in controlling the transition into mitosis.
Alison J. Lin - One of the best experts on this subject based on the ideXlab platform.
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Viral Mimicry of Cdc2/Cyclin-Dependent Kinase 1 Mediates Disruption of Nuclear Lamina during Human Cytomegalovirus Nuclear Egress
2013Co-Authors: Sofia Hamirally ¤a, Jeremy P. Kamil, Yasmine M. Ndassa-colday, Alison J. Lin, Wan Jin Jahng ¤b, Moon-chang Baek ¤c, Sarah Noton ¤d, Laurie A. Silva, Martha Simpson-holley ¤e, David M. KnipeAbstract:The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein Kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lamin A/C in vitro on sites targeted by Cdc2/Cyclin-Dependent Kinase 1, the enzyme that is responsible for breaking down the nuclear lamina during mitosis. Quantitative mass spectrometry analyses, comparing lamin A/C isolated from cells infected with viruses either expressing or lacking UL97 activity, revealed UL97-dependent phosphorylation of lamin A/C on the serine at residue 22 (Ser 22). Transient treatment of HCMV-infected cells with maribavir, an inhibitor of UL97 Kinase activity, reduced lamin A/C phosphorylation by approximately 50%, consistent with UL97 directly phosphorylating lamin A/C during HCMV replication. Phosphorylation of lamin A/C during viral replication was accompanied by changes in the shape of the nucleus, as well as thinning, invaginations, and discrete breaks in the nuclear lamina, all of which required UL97 activity. As Ser 22 is a phosphorylation site of particularly strong relevance for lamin A/C disassembly, our data support a model wherein viral mimicry of a mitoti
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viral mimicry of cdc2 cyclin dependent Kinase 1 mediates disruption of nuclear lamina during human cytomegalovirus nuclear egress
PLOS Pathogens, 2009Co-Authors: Sofia Hamirally, Jeremy P. Kamil, Alison J. Lin, Laurie A. Silva, Yasmine Ndassacolday, Wan Jin Jahng, Moonchang Baek, Sarah L Noton, Martha SimpsonholleyAbstract:The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein Kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lamin A/C in vitro on sites targeted by Cdc2/Cyclin-Dependent Kinase 1, the enzyme that is responsible for breaking down the nuclear lamina during mitosis. Quantitative mass spectrometry analyses, comparing lamin A/C isolated from cells infected with viruses either expressing or lacking UL97 activity, revealed UL97-dependent phosphorylation of lamin A/C on the serine at residue 22 (Ser22). Transient treatment of HCMV-infected cells with maribavir, an inhibitor of UL97 Kinase activity, reduced lamin A/C phosphorylation by approximately 50%, consistent with UL97 directly phosphorylating lamin A/C during HCMV replication. Phosphorylation of lamin A/C during viral replication was accompanied by changes in the shape of the nucleus, as well as thinning, invaginations, and discrete breaks in the nuclear lamina, all of which required UL97 activity. As Ser22 is a phosphorylation site of particularly strong relevance for lamin A/C disassembly, our data support a model wherein viral mimicry of a mitotic host cell Kinase activity promotes nuclear egress while accommodating viral arrest of the cell cycle.
Martha Simpsonholley - One of the best experts on this subject based on the ideXlab platform.
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viral mimicry of cdc2 cyclin dependent Kinase 1 mediates disruption of nuclear lamina during human cytomegalovirus nuclear egress
PLOS Pathogens, 2009Co-Authors: Sofia Hamirally, Jeremy P. Kamil, Alison J. Lin, Laurie A. Silva, Yasmine Ndassacolday, Wan Jin Jahng, Moonchang Baek, Sarah L Noton, Martha SimpsonholleyAbstract:The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein Kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lamin A/C in vitro on sites targeted by Cdc2/Cyclin-Dependent Kinase 1, the enzyme that is responsible for breaking down the nuclear lamina during mitosis. Quantitative mass spectrometry analyses, comparing lamin A/C isolated from cells infected with viruses either expressing or lacking UL97 activity, revealed UL97-dependent phosphorylation of lamin A/C on the serine at residue 22 (Ser22). Transient treatment of HCMV-infected cells with maribavir, an inhibitor of UL97 Kinase activity, reduced lamin A/C phosphorylation by approximately 50%, consistent with UL97 directly phosphorylating lamin A/C during HCMV replication. Phosphorylation of lamin A/C during viral replication was accompanied by changes in the shape of the nucleus, as well as thinning, invaginations, and discrete breaks in the nuclear lamina, all of which required UL97 activity. As Ser22 is a phosphorylation site of particularly strong relevance for lamin A/C disassembly, our data support a model wherein viral mimicry of a mitotic host cell Kinase activity promotes nuclear egress while accommodating viral arrest of the cell cycle.
Janmichael Peters - One of the best experts on this subject based on the ideXlab platform.
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mitotic regulation of the human anaphase promoting complex by phosphorylation
The EMBO Journal, 2003Co-Authors: Claudine Kraft, Franz Herzog, Karl Mechtler, Christian Gieffers, Anja Hagting, Jonathon Pines, Janmichael PetersAbstract:The anaphase‐promoting complex (APC) or cyclosome is a ubiquitin ligase that initiates anaphase and mitotic exit. APC activation is thought to depend on APC phosphorylation and Cdc20 binding. We have identified 43 phospho‐sites on APC of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7. In vitro , at least 15 of the mitotic phospho‐sites can be generated by cyclin‐dependent Kinase 1 (Cdk1), and 3 by Polo‐like Kinase 1 (Plk1). APC phosphorylation by Cdk1, but not by Plk1, is sufficient for increased Cdc20 binding and APC activation. Immunofluorescence microscopy using phospho‐antibodies indicates that APC phosphorylation is initiated in prophase during nuclear uptake of cyclin B1. In prometaphase phospho‐APC accumulates on centrosomes where cyclin B ubiquitination is initiated, appears throughout the cytosol and disappears during mitotic exit. Plk1 depletion neither prevents APC phosphorylation nor cyclin A destruction in vivo . These observations imply that APC activation is initiated by Cdk1 already in the nuclei of late prophase cells.
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the anaphase promoting complex proteolysis in mitosis and beyond
Molecular Cell, 2002Co-Authors: Janmichael PetersAbstract:Key events in mitosis such as sister chromatid separation and subsequent inactivation of Cyclin-Dependent Kinase 1 are regulated by ubiquitin-dependent proteolysis. These events are mediated by the anaphase-promoting complex (APC), a cell cycle-regulated ubiquitin ligase that assembles multiubiquitin chains on regulatory proteins such as securin and cyclins and thereby targets them for destruction by the 26S proteasome.
Gustavo Baldassarre - One of the best experts on this subject based on the ideXlab platform.
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stathmin a protein with many tasks new biomarker and potential target in cancer
Expert Opinion on Therapeutic Targets, 2011Co-Authors: Barbara Belletti, Gustavo BaldassarreAbstract:Introduction: Stathmin is a microtubule-destabilizing phosphoprotein, firstly identified as the downstream target of many signal transduction pathways. Several studies then indicated that stathmin is overexpressed in many types of human malignancies, thus deserving the name of Oncoprotein 18 (Op18). At molecular level, stathmin depolymerizes microtubules by either sequestering free tubulin dimers or directly inducing microtubule-catastrophe. A crucial role for stathmin in the control of mitosis has been proposed, since both its overexpression and its downregulation induce failure in the correct completion of cell division. Accordingly, stathmin is an important target of the main regulator of M phase, Cyclin-Dependent Kinase 1. Areas covered: Recent evidences support a role for stathmin in the regulation of cell growth and motility, both in vitro and in vivo, and indicate its involvement in advanced, invasive and metastatic cancer more than in primary tumors. Expert opinion: Many studies suggest that high ...
