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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p107wee1 protein kinase plays a central role in regulating the cell cycle of fission yeast. It mediates transmission of signal(s) related to the nutritional status of the cell to the p34cdc2 protein kinase, which is an active component of the MPF complex driving cells into mitosis. p107wee1 is itself subject to control by the products of other genes such as nim1+/cdr1+, win1+, and perhaps wis1+ and other wis+ genes. At present, the relationships between these genes and their possible roles in the mitotic control are unclear and must await further analysis (Fig. 5). It is likely that some of the gene products are concerned with the sensing and/or transmission of nutritional signals. p107wee1 negatively regulates the activity of p34cdc2, probably by direct tyrosine phosphorylation, and also appears to regulate the activities of the cdc1+ and cdc27+ gene products. The effects of nitrogen starvation and of wee1 mutations on conditional lethal mutations at the cdc1, cdc2, and cdc27 loci, taken together, support the largely speculative model shown in Figure 5. During the normal cycle, the balance between phosphorylated and dephosphorylated p34cdc2 changes such that at the appropriate time, p34cdc2 is activated and the cell enters mitosis. We suggest that the cdc1+ and cdc27+ products may be regulated in a similar way. Such a mechanism would ensure coordinated activation of these and perhaps other proteins required for the G2/M transition. There are, of course, many uncertainties, and these must await elucidation by biochemical and genetic analysis.
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PMID:New elements in the mitotic control of the fission yeast Schizosaccharomyces pombe. 181 10

The cdr1 gene in Schizosaccharomyces pombe was identified as a mutation affecting the nutritional responsiveness of the mitotic size control. cdr1 alleles have been further analyzed for genetic interactions with elements of the mitotic control pathway and cloned by plasmid rescue of a conditional lethal cdr1-76 cdc25-22 double mutant. These analyses show that the cdr1 gene is allelic to nim1, a gene identified as a high copy number plasmid suppressor of the mitotic control gene, cdc25. The gene structure for cdr1 differs from the described nim1 gene in the carboxyl-terminal portion of the gene. The published nim1 sequence encoded a product of predicted Mr 45,000, and included 356 amino acids from the amino-terminal region of the gene and 14 amino acids from a noncontiguous carboxyl-terminal fragment. The cdr1 sequence includes an additional 237 amino acids of the contiguous fragment and encodes a product of predicted Mr 67,000. The sequence shows a high level of identity with protein kinases over the amino-terminal catalytic domain, and limited identity with yeast protein kinases SNF1, KIN2 and KIN1 over part of the carboxyl-terminal domain. The effect of overexpression of the full length gene has been examined in various genetic backgrounds. These data show that the full length gene product is required to give a normal cell cycle response to nitrogen starvation. A detailed examination of the genetic interaction of cdr1 mutants with various mutants of mitotic control genes (cdc2, cdc25, wee1, cdc13) demonstrated strong interactions with cdc25, some cdc2 alleles, and with cdc13-117. Overall, the results are interpretable within the framework of the existing model of cdr1/nim1 action in mitotic control, i.e., cdr1 functions upstream of wee1 to relieve mitotic inhibition.
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PMID:Genetic and molecular analysis of cdr1/nim1 in Schizosaccharomyces pombe. 200 5

Earlier work has shown that there is a periodic change in the rate of production of CO2 during the cell cycle of fission yeast and that this periodicity persists after a block to the DNA-division cycle and also after a block to protein synthesis. It appears that there is a periodic control or 'oscillator' affecting CO2 production that is normally closely entrained to the cell cycle, but which can 'free-run' after a block. In this paper, we examine what events in the DNA-division cycle can generate the entrainment signals and what is the nature of such signals. In the first set of experiments, CO2 production was measured by manometry during induction synchrony produced by blocking the DNA-division cycle in an asynchronous culture for a period and then releasing the block. Synchronous cell division occurs after the release with cell cycles shorter than normal. After release from a block imposed by shifting up the mutant cdc2.33 to the restrictive temperature, oscillations in CO2 production started rapidly and remained closely entrained to the division cycles (with slightly different patterns and timing from those after selection synchrony). This showed that there was an entrainment signal but did not show whether it came from start, the S period or mitosis. A similar experiment with cdc10.129 showed that an early signal came from either start or the S period, as did an experiment with release from N-starvation. The results with cdc25.22 were similar to those with cdc2.33. After a block with hydroxyurea, there was entrainment but with no signs of the early signal that occurred with cdc10. This showed that the early signal came from start and not from the S period. In a second set of double-block experiments, the first block was followed by a second different block. With cdc25.22 followed by MBC (an inhibitor of nuclear division) the cells passed through a narrow window of the cell cycle between the transition point of cdc25.22 and mitosis. This was sufficient to start the oscillations, showing that an entrainment signal could be generated at about the time of mitosis. The results from using hydroxyurea followed by cdc2.33 showed no genuine oscillations, confirming the conclusion from the single hydroxyurea block. The results from using hydroxyurea followed by cdc10.129 confirmed the existence of a mitotic signal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:CO2 production after induction synchrony of the fission yeast Schizosaccharomyces pombe: the origin and nature of entrainment. 211 27

Fission yeast cell division is initiated by the cdc2/cdc13-cyclin protein kinase which in its catalytically active state comprises the mitotic inducer. During interphase the cdc2/cyclin complex is assembled in an inactive state that requires cdc25+ gene function for M-phase activation. The cdc25+ product, a 76 kd phosphoprotein, is shown to oscillate in abundance during the cell cycle, reaching a peak at G2/M, and to be sensitive to nitrogen starvation. The level of cdc25 is subject to feedback regulation involving both cdc25 and cdc2.
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PMID:Fission yeast cdc25 is a cell-cycle regulated protein. 217 10

A novel approach to the study of the control of the mammalian cell cycle was opened by the cloning of a human gene by complementation of a fission-yeast cdc2 cell-cycle mutant. We have investigated the behaviour of the RNA and protein products of this human gene, CDC2Hs, and its murine equivalent, CDC2Mm during serum starvation and re-feeding of cultured fibroblasts. In contrast to the pattern of wild-type cdc2+ expression in fission yeast previously described, the mammalian homologue displays variation in both RNA and protein levels during exit from and re-entry into the mitotic cycle. Like its yeast counterpart, however, the mammalian CDC2 protein (p34CDC2) becomes dephosphorylated upon shifting from exponential growth to quiescence, and rephosphorylated late in the G1 phase when cells are stimulated to re-enter the cycle. We propose that phosphorylation of p34CDC2 serves as a regulatory mechanism generally in eukaryotic cells, while transcriptional control of the CDC2 gene in higher eukaryotes may be relevant to long term processes such as senescence and differentiation.
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PMID:Regulated expression and phosphorylation of a possible mammalian cell-cycle control protein. 328 81

Genes encoding cdk1 (p34cdc2), cyclin A, cyclin B, and the tumor suppressor gene Rb are fundamental regulators of cell cycle progression which associate as a complex with the transcription factor E2F. Expression of many of these proteins has previously been shown to be repressed by okadaic acid, a specific inhibitor of protein phosphatases 1/2A (PP1/PP2A), resulting in growth arrest in nontransformed but immortalized cells. We have investigated levels of mRNA encoding cdk1 (p34cdc2), cyclin A, cyclin B, Rb, GAPDH, c-myc, and histone H4 genes for sensitivity to okadaic acid in HeLa cells to determine if transformation altered their regulation. Serum starvation slowed growth and diminished mRNA levels for all genes tested except c-myc and GAPDH. When starved cells were subsequently exposed to 19 nM okadaic acid or refed 10% serum, mRNA levels of cyclin A, cyclin B, cdk1, and Rb dramatically increased while mRNA levels for c-myc and GAPDH were largely unaffected. Histone H4 mRNA levels and the rate of DNA synthesis were greatly enhanced by serum addition but not affected appreciably by okadaic acid. Okadaic acid was also effective in blocking proliferation of exponentially growing HeLa cells at G2/M and S phase. Despite the cell cycle phase-specific block, elevated mRNA levels for cdk1, cyclin A, cyclin B, Rb, and suppression of H4 mRNA levels were detected and persisted for at least 12 hr following okadaic acid removal. The results demonstrate that cell cycle progression is blocked and several cell cycle regulatory genes, encoding transcription factor E2F-associated proteins, experience elevation of mRNA levels through mechanisms sensitive to okadaic acid likely through a PP1/PP2A-sensitive mechanism. Data from transformed cells contrast with data from immortalized but nontransformed cells in which okadaic acid also blocks cell cycle progression during G2/M phase but suppresses expression of these genes. Such contrasts may be correlated with reduced growth factor dependence and transformation.
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PMID:Selective induction of cell cycle regulatory genes cdk1 (p34cdc2), cyclins A/B, and the tumor suppressor gene Rb in transformed cells by okadaic acid. 762 88

Human myeloid leukemia cells, such as HL60, U937, and THP1 cells, undergo macrophage differentiation and growth arrest following treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Surprisingly, we find that growth of a significant percentage of THP1 cells is arrested in the G2 phase of the cell cycle. G2 arrest correlates with cell-specific repression of the gene encoding p34cdc2, a crucial regulator of G2/M progression. Intriguingly, TPA-mediated repression of the cdc2 promoter was independent of the transcription factor E2F, distinguishing this pathway from mechanisms responsible for repression of cdc2 transcription in response to serum starvation. The region of the cdc2 promoter required for repression was located from bp -22 to -2 from the major transcriptional start site. This sequence, which we term the R box, directs the uncoupling of the basal promoter from upstream activators following TPA treatment. Analysis of THP1 nuclear proteins revealed a 55-kDa protein that was induced by TPA and interacted with the cdc2 promoter in an R-box-dependent manner. These observations provide evidence for the existence of cell-type- and promoter-specific pathways for the assembly of stable transcriptional initiation complexes that function to differentially regulate the expression of cell cycle control genes in mammalian cells.
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PMID:Identification of a cell-type-specific and E2F-independent mechanism for repression of cdc2 transcription. 776 Aug 24

A key component of Cdc2/Cdk2-activating kinase (CAK) is p40MO15, a protein kinase subunit that phosphorylates the T161/T160 residues of p34cdc2/p33cdk2. The level and activity of p40MO15 were essentially constant during cleavage of fertilised Xenopus eggs and in growing mouse 3T3 cells, but serum starvation of these cells reduced both the level and activity of p40MO15. Although the level and activity of endogenous p40MO15 did not vary in the cell cycle, we found that bacterially expressed p40MO15 was activated more rapidly by M-phase cell extracts than by interphase cell extracts. Bacterially expressed p40MO15 was phosphorylated mainly on serine 170 (a p34cdc2 phosphorylation site) by mitotic cell extracts, but mutation of S170 to alanine did not affect the activation of p40MO15, whereas mutation of T176 (the equivalent site to T161/T160 in p34cdc2/p33cdk2) abolished the activation of P40MO15. These studies suggest that the level and activity of p40MO15 is probably not a major determinant of p34cdc2/p33cdk2 activity in the cell cycle, and that the activation of p40MO15 may require phosphorylation on T176.
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PMID:Cell cycle regulation of the p34cdc2/p33cdk2-activating kinase p40MO15. 787 47

Butyrolactone I is a selective inhibitor of the cyclin-dependent kinase (cdk) family. It inhibits both cdk2 and cdc2 kinase, but scarcely affects C-kinase, A-kinase, casein kinases, MAP kinase or EGF receptor-tyrosine kinase (Kitagawa et al., 1993, Oncogene, 8, 2425-2432). We studied the effects of butyrolactone I on the cell cycle as well as on phosphorylation of retinoblastoma protein (pRB). Butyrolactone I inhibited phosphorylation of pRB catalyzed by cyclin A-cdk2 produced by baculovirus in vitro. Furthermore, it inhibited phosphorylation of pRB and cell cycle progression from G1 to S phase in WI38 cell cultures. WI38 cells arrested at the G0 phase by serum starvation progressed in the cell cycle after serum stimulation. pRB was phosphorylated after 10 h serum stimulation. Incorporation of [3H]thymidine into the cells began to increase after 16 h serum stimulation. These processes were inhibited by butyrolactone I. Flow cytometric analysis showed that exposure to butyrolactone I inhibited progression of the cell cycle from G1 to S phase. These data suggested that initiation of DNA synthesis was inhibited by butyrolactone I and that the cell cycle was arrested in the G1 phase. Butyrolactone I also inhibited H1 histone phosphorylation in human WI38 cells and their G2/M progression. tsFT210 cells, a temperature-sensitive cdc2 mutant cell line, were synchronized at G2/M at a nonpermissive temperature, butyrolactone I inhibited the cell cycle progression of these cells at G2/M at the permissive temperature. Thus butyrolactone I, a cyclin-dependent kinase family inhibitor, which prevented the phosphorylations of the cell cycle-regulating proteins pRB and H1 histone, inhibited the cell cycle at G1/S and G2/M, respectively. These results suggest that the phosphorylations of pRB and H1 histone may play crucial roles in G1/S and G2/M progression, respectively, although it is possible that phosphorylations of other proteins by cdks are involved in G1/S and G2/M progression.
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PMID:A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. 805 18

It has been suggested that cell-type determination in Dictyostelium discoideum is dependent on the position of a cell in the cell cycle at the time of starvation. In order to understand the molecular basis of this phenomenon, we initiated studies on the cell cycle and have recently described the isolation of a Dictyostelium gene encoding a homolog of the Cdc2 kinase. We have been unable to isolate additional cdc2 genes from Dictyostelium using polymerase chain reaction technology, but have isolated a gene that is highly related to cdc2. The encoded product is a protein of 33 kDa that shares over 60% identity to the cell-cycle-dependent Cdc2 kinases. However, despite this high level of identity, the gene is not capable of complementing the temperature-sensitive cdc28 mutant of Saccharomyces cerevisiae. Furthermore, the gene product shares some characteristics with the recently described PCTAIRE proteins; it contains a PCTAIRE motif instead of the Cdc2 kinase conserved PSTAIRE sequence, it does not possess the conserved GDSEID sequence that is involved in the activation of the enzyme and it has a Ser in the position equivalent to Thr-161. However, the Dictyostelium protein exhibits a slightly higher level of identity to the Cdc2 kinases than to the PCTAIRE proteins and is smaller than any of the PCTAIRE proteins thus far identified. Since the gene product has characteristics of both Cdc2 kinases and PCTAIRE proteins we have designated the gene product Crp (Cdc2-Related PCTAIRE) kinase. The gene is expressed as two transcripts of 1.5 and 1.8 kb and the expression is developmentally regulated with low levels of mRNA in vegetative cells and significantly higher levels throughout the remainder of the differentiation process. These results suggest the possibility that the gene product is involved in Dictyostelium differentiation rather than growth. This report is the first evidence for a highly-related cdc2 gene in unicellular eukaryote. It also demonstrates for the first time that a unicellular eukaryote expresses a protein containing the PCTAIRE sequence.
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PMID:The isolation from a unicellular organism, Dictyostelium discoideum, of a highly-related cdc2 gene with characteristics of the PCTAIRE subfamily. 821 53


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