Cell Cycle-regulated Expression, Phosphorylation, and Degradation of p55Cdc

p55Cdc is a mammalian protein that shows high homology to the cell cycle proteins Cdc20p of Saccharomyces cerevisiae and the product of the Drosophila fizzy(fzy) gene, both of which contain WD repeats and are thought to be required for the metaphase-anaphase transition. Thefzy mutants exhibit a metaphase arrest phenotype, which is accompanied by stabilization of cyclins A and B, leading to the hypothesis that fzy function is required for cell cycle-regulated ubiquitin-mediated proteolysis. p55Cdc expression was initiated at the G1/S transition and steady state levels of p55Cdc were highest at M and lowest in G1. Inhibition of the 26 S proteasome prevented both mitotic exit and loss of p55Cdc at the M/G1 transition, suggesting that p55Cdc degradation was mediated by the cell cycle-regulated proteolytic pathway. Immune complexes of p55Cdc obtained at different cell cycle stages showed a variety of proteins with dramatic differences observed in the pattern of associated proteins during the transition from G2 to M. Immunolocalization of p55Cdc demonstrated dynamic changes in p55Cdc localization as the cells transit mitosis. p55Cdc appears to act as a regulatory protein interacting with several other proteins, perhaps via its seven WD repeats, at multiple points in the cell cycle. p55Cdc is a mammalian protein that shows high homology to the cell cycle proteins Cdc20p of Saccharomyces cerevisiae and the product of the Drosophila fizzy(fzy) gene, both of which contain WD repeats and are thought to be required for the metaphase-anaphase transition. Thefzy mutants exhibit a metaphase arrest phenotype, which is accompanied by stabilization of cyclins A and B, leading to the hypothesis that fzy function is required for cell cycle-regulated ubiquitin-mediated proteolysis. p55Cdc expression was initiated at the G1/S transition and steady state levels of p55Cdc were highest at M and lowest in G1. Inhibition of the 26 S proteasome prevented both mitotic exit and loss of p55Cdc at the M/G1 transition, suggesting that p55Cdc degradation was mediated by the cell cycle-regulated proteolytic pathway. Immune complexes of p55Cdc obtained at different cell cycle stages showed a variety of proteins with dramatic differences observed in the pattern of associated proteins during the transition from G2 to M. Immunolocalization of p55Cdc demonstrated dynamic changes in p55Cdc localization as the cells transit mitosis. p55Cdc appears to act as a regulatory protein interacting with several other proteins, perhaps via its seven WD repeats, at multiple points in the cell cycle. In eukaryotic cells, different complexes of kinases and their associated activating or inhibitory proteins control progression through discrete steps of the cell cycle. The best understood complexes known to play a central role in cell cycle progression are the cyclins in association with their cyclin-dependent kinases (Cdks) 1The abbreviations used are: Cdk, cyclin-dependent kinase; CENP, centromere protein; LLnL,N-acetylleucylnorleucinal; E64d, (2S,3S)-trans-epoxysuccinyl-l-leucylamido-3-methyl-butane ethyl ester; DCB, dihydrocytochalasin B; S100, 100,000 ×g supernatant; P100, 100,000 × g pellet; Plk, Polo-like kinase; PAGE, polyacrylamide gel electrophoresis; BSA, bovine serum albumin; PBS, phosphate-buffered saline; TD, telophase disc; FITC, fluorescein isothiocyanate. (reviewed in Refs.1Morgan D.O. Nature. 1995; 374: 131-134Crossref PubMed Scopus (2955) Google Scholar, 2Sherr C.J. Cell. 1994; 79: 551-555Abstract Full Text PDF PubMed Scopus (2603) Google Scholar, 3Sherr C.J. Roberts J.M. Genes Dev. 1995; 9: 1149-1163Crossref PubMed Scopus (3227) Google Scholar). In addition to regulation by phosphorylation and association with Cdk inhibitors, the cyclin-Cdk complexes are subject to a more irrevocable form of regulation, i.e. the degradation of cyclin via the cell cycle-regulated ubiquitin-mediated proteolytic pathway (4Glotzer M. Murray A.W. Kirschner M.W. Nature. 1991; 349: 132-137Crossref PubMed Scopus (1914) Google Scholar, 5Hershko A. Ganoth D. Pehrson J. Palazzo R.E. Cohen L.H. J. Biol. Chem. 1991; 266: 16376-16379Abstract Full Text PDF PubMed Google Scholar, 6Holloway S.L. Glotzer M. King R.W. Murray A.W. Cell. 1993; 73: 1393-1402Abstract Full Text PDF PubMed Scopus (490) Google Scholar, 7King R.W. Deshaies R.J. Peters J.M. Kirschner M.W. Science. 1996; 274: 1652-1659Crossref PubMed Scopus (1122) Google Scholar). The work of a number of laboratories has recently converged to identify three tetratricopeptide proteins, CDC16, CDC23, and CDC27, as components of the E3 complex that becomes activated during Ganoth D. A. J. A. Biol. 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Science. 1996; 274: 1652-1659Crossref PubMed Scopus (1122) Google Scholar). and are mammalian proteins expression at exhibit dynamic changes in their localization at different mitotic and are J. Biol. 1994; PubMed Scopus Google Scholar, R.J. J. Biol. 1995; PubMed Scopus Google Scholar). In mitotic exit the of the cell cycle-regulated protein J. 1995; PubMed Scopus Google and the of has to the product of the gene, a protein that is the metaphase-anaphase transition Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of proteins the cyclin which the A and cyclins for (4Glotzer M. Murray A.W. Kirschner M.W. Nature. 1991; 349: 132-137Crossref PubMed Scopus (1914) Google Scholar). J. J. Cell. Biol. 1994; PubMed Scopus Google a which appears to be a mammalian of of the Saccharomyces cerevisiae D. Cell. Biol. 1991; PubMed Google Drosophila fzy J. Biol. 1995; PubMed Scopus Google and the Cell. Biol. PubMed Scopus Google to the their WD repeats C.J. Nature. 1994; PubMed Scopus Google Scholar). mutants arrest in at the the of a and to the the cell and a Biol. PubMed Scopus Google Scholar). has that the is required for of by the of or by D. Cell. Biol. 1991; PubMed Google M. Biol. Cell. PubMed Scopus Google Scholar). The fzy mutants demonstrated that the to cyclins A and B, and the of to is to a of protein J. Biol. 1995; PubMed Scopus Google Scholar, J. 1995; PubMed Scopus Google Scholar). J. Biol. 1995; PubMed Scopus Google that function is required for cell cycle-regulated ubiquitin-mediated mutants are in and from arrest Cell. Biol. PubMed Scopus Google Scholar). The high of homology and as as their role in cell has the that are of a the WD J. Biol. 1995; PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar). p55Cdc several that are with its role in the cell cycle. in or cells, is in p55Cdc appears to be for cell of p55Cdc cells in of cells that exhibit a in p55Cdc in the J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). Immune complexes of p55Cdc a protein that was in cells in cells and with the cell cycle. of p55Cdc in cells and suggesting that p55Cdc regulation is for cell cycle control during cell and M. A. J. 1996; Google Scholar). was to the and localization of p55Cdc at different stages of the mammalian cell cycle. The mitotic Cdk, was in and as control in the of with showed that both the and phosphorylation of p55Cdc were at and at with a in phosphorylation during the G2 to M transition. obtained from different cell cycle stages and showed A steady of p55Cdc during the of the cell cycle in loss at the M to transition. loss be prevented by a 26 S proteasome suggesting that p55Cdc be cell cycle protein to be by the cell cycle-regulated ubiquitin-mediated proteolytic pathway. of p55Cdc by dynamic changes during from the at mitotic in to the in a role for p55Cdc in G2 M. and cells were in or with bovine and cells were at the of S by the Cell. Biol. PubMed Scopus Google Scholar). S cells were G2 cells were and mitotic cells were obtained by from the The was the a the cells of were and in of cells and the cells to the by the cells were The cells were used for cells at the M/G1 transition, cells were The cells were in or with the (2S,3S)-trans-epoxysuccinyl-l-leucylamido-3-methyl-butane ethyl or dihydrocytochalasin a the cells were for by and for cyclin B, and by was cells that for with to a of cells in and S cells were in by the cells for in serum The cells were activated by addition of serum to the and the cells were at were with and serum for by in the The for the was for a in The was at a of were obtained by the cells in a and a in were from The cells were for with and the with a cell The were by a × g in a for The was and by for at 100,000 The and were in J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). and were to the to its to the other The and were for at × a for of a cell has J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). were at The of the a has J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). were the of p55Cdc to were by through a to which the The was with of PBS, and the were with The of the was to and were in at were with the The for has J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). The of was to of for the protein and to of for the The of the control was that of the to cyclin A cyclin and the of were from The to cyclin was from and the to was from The was by cell were in × Nature. PubMed Scopus Google at a of The were as that the was that was by cell number for three The proteins were to for at with the The proteins were by the of cells was in for and for in serum and and in PBS, The cells were with p55Cdc and of from or control for The were in PBS, and with serum in with to and was for were in PBS, and in The were in and in were observed with a with a at mitotic stages were with the were at work demonstrated that p55Cdc expression was in a of J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). identify the of the cell cycle at which p55Cdc expression is a cell was cells were at by serum and to the cell cycle by the addition of serum to the cells S serum and at M. J. J. J. Biol. 1993; PubMed Scopus Google Scholar). serum the cells were with and with p55Cdc or for The in the of p55Cdc and a at with the of The a of which be to cyclin A. both p55Cdc and were of has to at the G1/S transition C.J. Nature. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar). the of of cells was for and cell or were or of and in a the of p55Cdc at and the the of p55Cdc to be by a loss that of the with p55Cdc at and showed loss of the of the showed a to the is in with the of for protein A. PubMed Scopus Google Scholar). of the of p55Cdc at different showed to be for of p55Cdc of the and showed the in to be The a of the of its at the p55Cdc was or from the to the and a showed a in the and and and of the form the showed a steady loss of the high be with the phosphorylation of to or the cell cycle-regulated and phosphorylation of cells were and at stages of the cell cycle the cells were and the p55Cdc is known to be associated with protein which with the cell cycle J. J. Cell. Biol. 1994; PubMed Scopus Google and to different be of to p55Cdc complexes from the and of p55Cdc in cells was in and through the cell cycle to at G2 The regulation of p55Cdc was to that of at and at The p55Cdc showed the of a protein in the and through the cell cycle. The showed a that to with p55Cdc and be to cyclin A A in the of has observed as cells from to G2 Cell. Biol. PubMed Scopus Google Scholar). the of was in the p55Cdc the highest in the and pattern with the cell cycle. the in the G2 was the that in the and of mitotic cells was of the The of cells with for at different stages of the cell cycle are in The G2 cells the the mitotic cells by has cells that and G1. p55Cdc phosphorylation is in of the obtained from a of cells, by in phosphorylation of p55Cdc as the cells from to The p55Cdc from and contain a of that with the form of and is in the mitotic The showed a at which different of Immune complexes obtained from the with protein showed a that was by the p55Cdc the has in the mitotic cells, the and were The mitotic showed a of proteins in the the of proteins of and The was obtained by different to p55Cdc and The of phosphorylation in the from different stages in the cell cycle and that of was during G1. in the of phosphorylation at G2 has observed D. Cell. Full Text PDF PubMed Scopus Google Scholar). The obtained in were to and the are in for the G2 both proteins exhibit the highest of protein in the is in the and were obtained for the of in the showed form of in the the associated with cell be in a is with the that the inhibitory that both and is a A. Science. 1995; PubMed Scopus Google Biol. PubMed Scopus Google Scholar). In is that cyclin has to the M. M. J. J. 1995; PubMed Scopus Google Scholar). The phosphorylation of both p55Cdc and at G2 and a dramatic at M. p55Cdc showed in transition from G2 to the showed in phosphorylation of p55Cdc during state levels of cell from or cells were for as and A G2 was used to P100, obtained from × cells and from × cells were for The were with p55Cdc cyclin A and cyclin of p55Cdc cell from and × cells were and for with p55Cdc of cell from × cells and P100, from × were of the were with three different to as a to as a and protein and to as a protein the steady state levels of p55Cdc at different points in the cell cells were and in The was by cell number and protein and of protein in the cells were a and the was and were with cyclin and cyclin A The demonstrated that p55Cdc was at a in with the other stages of the cell cycle. The of p55Cdc as the cells through the cell cycle and at M. was by a dramatic loss of p55Cdc as the cells a cycle at G1. In cyclin A and a dramatic A at G1/S and was at a high through is in with that of Science. PubMed Scopus Google with that of and J. Nature. PubMed Scopus Google observed a in cyclin A levels to from their were for protein and cell The cyclin levels at G1/S and as observed Science. PubMed Scopus Google Scholar). of a G2 by cell showed that both cyclin A and are in the as observed by J. J. Biol. 1991; PubMed Scopus Google Scholar, M. J. Roberts J.M. M. Cell. Biol. 1995; PubMed Scopus Google Scholar). The of p55Cdc to be in three in the protein was was in the showed a the cell cycle for the in the and A. PubMed Scopus Google and through the is protein from the cycle. of the p55Cdc used in is in of cell was in and and the with the p55Cdc protein A at and a at were The be to p55Cdc as J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). A with p55Cdc The the of the and that the proteins in the p55Cdc complexes and are to The of the obtained by the of cell by is in cell was in and S100, P100, and in The as a for the was a for both and and the protein was a for the the the in the the protein in the and and the demonstrated that protein is in the the of the was to the of p55Cdc loss that observed by of cells at cell cycle that at or and S were to their cell cycle progression in the or of a variety of The has to cyclin degradation and cell cycle arrest in and cells J. A. 1993; PubMed Scopus Google and has used as a 26 S proteasome in M. J. 1996; PubMed Scopus Google Scholar, M. M. Science. 1995; PubMed Scopus Google Scholar, D. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, J. 1996; PubMed Scopus Google Scholar). The and and is a control to the 26 S proteasome and cell cycle M. M. Science. 1995; PubMed Scopus Google Scholar, R.J. M. Roberts J.M. 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Nature. 1991; 349: 132-137Crossref PubMed Scopus (1914) Google Scholar, 7King R.W. Deshaies R.J. Peters J.M. Kirschner M.W. Science. 1996; 274: 1652-1659Crossref PubMed Scopus (1122) Google Scholar). p55Cdc cyclin showed with the in the the to a cyclin J. 1996; PubMed Scopus Google or a cyclin with to the of R.J. M. Roberts J.M. Genes Dev. 1996; PubMed Scopus Google Scholar). the levels of were by of the and the in its high form from arrest a of as by the the and and The that showed a of was by of its to the of both and A complexes PubMed Scopus Google Scholar). The cells from arrest showed p55Cdc with of the with cells with that the cell cycle-regulated p55Cdc degradation is at the M to transition and has by the the cells are in and S of the cell cycle. was to the of p55Cdc during mitotic The of p55Cdc and at mitotic stages is in The of p55Cdc in mitotic cells was more that in cells in mitotic to with the of the to the mitotic The of was at at which to be to the centromere of the as a Science. 1995; PubMed Scopus Google Scholar). The of cells p55Cdc localization during mitotic the are with their from the centromere which at the of the of the Science. 1995; PubMed Scopus Google Scholar). p55Cdc appears to be to the centromere and cell the cells metaphase p55Cdc to the mitotic and the both a and was from the by the the with has to the of by the association be during with p55Cdc as a at the which as the cells were in and telophase and The as in in to the in a of p55Cdc at the of p55Cdc was at its highest during and metaphase and that by was to the levels in The of p55Cdc was was to with the during and telophase was cells with the p55Cdc was with the control p55Cdc The the of p55Cdc at the during mitotic p55Cdc was to the p55Cdc was at the with the used in p55Cdc is a cell cycle protein that is in of cells J. J. Cell. Biol. 1994; PubMed Scopus Google and of a of cells, during expression pattern is with that of the of which is initiated at the G1/S transition C.J. Nature. PubMed Scopus Google Scholar, A. PubMed Scopus Google and the of Science. PubMed Scopus Google that expression of of cells to is with the to S transition as of of that at that the of p55Cdc at the G1/S transition be of a The role of p55Cdc at transition and in S is p55Cdc are associated with multiple protein with the protein in the and the protein with the J. J. Cell. Biol. 1994; PubMed Scopus Google Scholar). was to in to identify protein for p55Cdc has a of in of p55Cdc and dynamic changes in their with The p55Cdc the to in the and the shows a exit from the shows a protein in association with p55Cdc in the and through the of the cell cycle. is that association is observed in a of cells is that p55Cdc with different proteins at different during the cell a dramatic in the pattern of associated proteins in the transition from G2 to M The of that both the and phosphorylation of p55Cdc are cell at and with the of the cell cycle to at The p55Cdc cycle appears to to the p55Cdc protein cycle. is or of The of the Drosophila fzy as a of p55Cdc and a for p55Cdc p55Cdc and to the homology that the WD repeats J. Biol. 1995; PubMed Scopus Google Scholar). The that the metaphase arrest by fzy is associated with to both mitotic cyclins A and has to the function is required for cell cycle-regulated J. Biol. 1995; PubMed Scopus Google Scholar). 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