p55CDC25 is a nuclear protein required for the initiation of mitosis in human cells.

Abstract

The cdc25+ gene of fission yeast encodes a phosphotyrosine phosphatase that dephosphorylates tyrosine-15 of p34CdC2 and thereby activates p34`2/cyclin to bring about entry into M phase. We have recently cloned a human homolog, CDC25, which rescues the M-phase initiation defect of yeast cdc25 temperature-sensitive mutants. Antibodies raised against the CDC25 gene product specifically recognize human proteins of -55 and -52 kDa. Micro'niection of affinity-purified anti-CDC25 antibodies into HeLa cells inhibits entry into mitosis. These observations suggest that the CDC25 gene products are essential for the initiation of mitosis in human cells, similar to their homologs in fission yeast and Drosophila. CDC25 gene products, like p34CDC2, are localized primarily in the nucleus during interphase, suggesting that activation of p34CDC2/cyclin by p52/p55CDC2S occurs within the nucleus.The molecular events that trigger the onset ofmitosis have for many years remained elusive. Recently, progress has been achieved primarily from two lines of research: the biochemical characterization of a protein complex called M-phase promoting factor that induces M phase in animal oocytes and genetic and molecular studies of cell cycle mutants in yeast (1). These studies have revealed that the onset of mitosis is brought about by a universally conserved serine/threonine protein kinase that consists of two subunits: a 34-kDa catalytic subunit encoded by the cdc2+ gene and a 45-to 60-kDa regulatory subunit, which is member of the cyclin family of proteins (2).The p34cDC2/cyclin kinase is assembled in an inhibited state during interphase, and its activation is widely believed to be the critical step in the initiation of mitosis (1, 2). By using the genetically tractable fission yeast Schizosaccharomyces pombe, it has been possible to identify a number of proteins that are dose-dependent regulators of mitosis. The intracellular concentration of these proteins modulates the size at which cells initiate mitosis, thereby coordinating growth with cell cycle progression. The two most important dose-dependent regulators appear to be p80cdc25 and p107wee1 (3,4). The weel+ product, p107wee1, is a serine/tyrosine kinase that inhibits the initiation of mitosis by directly or indirectly promoting the phosphorylation of p34Cc2 on tyrosine-15 and thereby rendering the kinase inactive (4-8).Acting in opposition to p107wee1 is the p8ocdc25 mitotic inducer. Increased production of p80cdc25 causes mitosis to initiate at an abnormally small size (3). In the absence of p8Ocdc25, fission yeast cells arrest in late G2 with an elongated phenotype and a tyrosine phosphorylated form of p34cdc2 harboring low kinase activity (7, 9, 10). Recent evidence that purified cdc25 protein cannot only directly stimulate the dephosphorylation and activation of p34c2/cyclin in enriched fractions (11) as well as purified complexes (12), but can also dephosphorylate para-nitrophenylphosphate and other protein substrates in vitro, has confirmed that it is a protein phosphata...

K vitamins, PTP antagonism, and cell growth arrest

“…Among them, Cdc25 protein phosphatases are believed to be important regulators in control of cell cycle progression by activating cyclin-dependent kinases (Cdk) (Nilsson and Hoffman, 2000). Three Cdc25 homologs have been found in mammals, Cdc25A, Cdc25B, and Cdc25C (Sadhu et al, 1990;Millar et al, 1991;Nagata et al, 1991). Both Cdc25B and Cdc25C are thought to be regulators of G2/M transition through their ability to dephosphorylate and activate the Cdk1/cyclin B mitotic kinase complex, which is required for cell entry into mitosis (Nilsson and Hoffman, 2000) (Fig.…”

p53 downregulates expression of the G1/S cell cycle phosphatase Cdc25A

“…They are able to dephosphorylate both phosphoserines/threonines and phosphotyrosines on the same protein substrate. Cdc25B or Cdc25C regulate the transition from G 2 phase to mitosis through Cdk1 dephosphorylation (Millar et al, 1991;Strausfeld et al, 1994;Lammer et al, 1998). Cdc25A mainly activates Cdk2 and thereby induces progression from G 1 to S phase.…”

Chromosome condensation caused by loss of RCC1 function requires the cdc25C protein that is located in the cytoplasm.

“…Although all cdc25 genes rescue a S. pombe ts mutant, cdc25-22, they are supposed to have a different function in the cell cycle. For instance, the cdc25C protein is considered to be involved for the initiation of mitosis (Millar et al, 1991a) and the cdc25A protein is suggested to function after initiation of mitosis (Galaktionov and Beach, 1991). We chose the cdc25C as a possible cdc25 protein required for PCC induced by loss of RCC1 function.…”