Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Late infantile neuronal ceroid lipofuscinosis, LINCL, is one of the most common pediatric neurodegenerative disorders. It is caused by mutations in the CLN2 gene, which encodes a lysosomal pepstatin-insensitive peptidase (LPIP). We have identified a novel mutation, T523-1G --> A, by molecular analyses of three unrelated LINCL cases. The mutation was found to affect a 3' intronic splicing acceptor site, resulting in an aberrant mRNA with an insertion of 146 bp of intronic sequence. This causes a frame shift, produces a nonfunctional truncated protein, and results in LINCL.
Mol Genet Metab 1999 Jun
PMID:Late infantile neuronal ceroid lipofuscinosis is due to splicing mutations in the CLN2 gene. 1035 16

The Saccharomyces cerevisiae RAD6 (UBC2 ) gene encodes a ubiquitin-conjugating enzyme that is involved in a wide range of cellular processes including DNA repair, sporulation and N-end rule protein degradation. Under mild heat stress conditions (37-38 degrees C) rad6 null and rad6-149 mutant cells are unable to grow. The molecular basis for this failure to grow is unknown. Here we show that the heat sensitivity of rad6 mutants is not due to cell death but to an inability to progress in the cell cycle. The temperature-induced cell cycle arrest of these mutants is due to a block in a branch of the RAD6 pathway distinct from the DNA repair and the N-end rule protein degradation pathways. Wild-type cells heated to 38 degrees C arrest transiently in the late G1 phase and then resume growth. At 38 degrees C rad6 mutant cells arrest in late G1 but, unlike wild-type cells, are unable to resume cell cycle progression. In both wild-type and in rad6 mutant cells, CLN1 and CLN2 transcript levels fall sharply upon temperature increase. In wild-type cells levels of these transcripts recover rapidly, whereas in the rad6 mutant they recover slowly. As rad6 cells remain arrested even after CLN1 and CLN2 mRNAs regain their preheat stress levels, factors additional to reduced G1 cyclin gene expression must cause the temperature-induced cell cycle block of the mutant. To identify genes involved in the relief of the cell cycle arrest under heat stress, we screened a multicopy yeast genomic library for clones that restore the growth of the rad6-149 mutant. A plasmid was isolated carrying the WSC2 gene, which is closely related to WSC1/SLG1/HCS77, a putative membrane heat sensor. Overexpression of WSC2 reverses the heat-induced cell cycle arrest of rad6-149 but not of rad6 null mutants. Taken together the findings point to the existence of an unidentified heat stress-activated cell cycle checkpoint pathway, which is antagonized by Rad6p by a mechanism also involving Wsc2p.
Mol Microbiol 1999 May
PMID:Heat-induced cell cycle arrest of Saccharomyces cerevisiae: involvement of the RAD6/UBC2 and WSC2 genes in its reversal. 1036 Dec 77

The role of mild oxidative stresses elicited by diethylmaleate (DEM)-induced glutathione depletion in the progression of the yeast cell cycle has been investigated. We found that different wild-type strains are sensitive to oxidative stresses induced by similar DEM doses: approximately 1 mM on YPD plates, 5-10 mM in shaken flasks. At lower doses, DEM caused a transient decrease in growth rate, largely because of a decreased G1-to-S transition. Treatment with higher DEM doses leads to complete growth arrest, with most cells found in the unbudded G1 phase of the cell cycle. DEM treatment resulted in transcriptional induction of stress-responsive element (STRE)-controlled genes and was relieved by treatment with the antioxidant N-acetyl cysteine. Reciprocal shift experiments with cdc25 and cdc28 mutants showed that the major cell cycle arrest point was located in the Start area, at or near the CDC25-mediated step, before the step mediated by the CDC28 cyclin-dependent kinase. The DEM-induced G1 arrest requires a properly regulated RAS pathway and can be bypassed by overexpressing the G1-specific cyclin CLN2. However, cells with either a deregulated RAS pathway or overexpressing CLN2 failed to grow and arrested as budded cells, indicating that a second DEM-sensitive cell cycle step exists.
Mol Microbiol 1999 May
PMID:In budding yeast, reactive oxygen species induce both RAS-dependent and RAS-independent cell cycle-specific arrest. 1036 Dec 79

In Saccharomyces cerevisiae, gene expression in the late G(1) phase is activated by two transcription factors, SBF and MBF. SBF contains the Swi4 and Swi6 proteins and activates the transcription of G(1) cyclin genes, cell wall biosynthesis genes, and the HO gene. MBF is composed of Mbp1 and Swi6 and activates the transcription of genes required for DNA synthesis. Mbp1 and Swi4 are the DNA binding subunits for MBF and SBF, while the common subunit, Swi6, is presumed to play a regulatory role in both complexes. We show that Stb1, a protein first identified in a two-hybrid screen with the transcriptional repressor Sin3, binds Swi6 in vitro. The STB1 transcript was cell cycle periodic and peaked in late G(1) phase. In vivo accumulation of Stb1 phosphoforms was dependent on CLN1, CLN2, and CLN3, which encode G(1)-specific cyclins for the cyclin-dependent kinase Cdc28, and Stb1 was phosphorylated by Cln-Cdc28 kinases in vitro. Deletion of STB1 caused an exacerbated delay in G(1) progression and the onset of Start transcription in a cln3Delta strain. Our results suggest a role for STB1 in controlling the timing of Start transcription that is revealed in the absence of the G(1) regulator CLN3, and they implicate Stb1 as an in vivo target of G(1)-specific cyclin-dependent kinases.
Mol Cell Biol 1999 Aug
PMID:Regulation of transcription at the Saccharomyces cerevisiae start transition by Stb1, a Swi6-binding protein. 1040 18

The general transcription factor TFIID, which is composed of TATA-binding protein (TBP) and an array of TBP-associated factors (TAFs), has been shown to play a crucial role in recognition of the core promoters of eukaryotic genes. We isolated Saccharomyces cerevisiae yeast TAF145 (yTAF145) temperature-sensitive mutants in which transcription of a specific subset of genes was impaired at restrictive temperatures. The set of genes affected in these mutants overlapped with but was not identical to the set of genes affected by a previously reported yTAF145 mutant (W.-C. Shen and M. R. Green, Cell 90:615-624, 1997). To identify sequences which rendered transcription yTAF145 dependent, we conducted deletion analysis of the TUB2 promoter using a novel mini-CLN2 hybrid gene reporter system. The results showed that the yTAF145 mutations we isolated impaired core promoter recognition but did not affect activation by any of the transcriptional activators we tested. These observations are consistent with the reported yTAF145 dependence of the CLN2 core promoter in the mutant isolated by Shen and Green, although the CLN2 core promoter functioned normally in the mutants we report here. These results suggest that different promoters require different yTAF145 functions for efficient transcription. Interestingly, insertion of a canonical TATA element into the TATA-less TUB2 promoter rescued impaired transcription in the yTAF145 mutants we studied. It therefore appears that strong binding of TBP to the core promoter can alleviate the requirement for at least one yTAF145 function.
Mol Cell Biol 2000 Apr
PMID:Impaired core promoter recognition caused by novel yeast TAF145 mutations can be restored by creating a canonical TATA element within the promoter region of the TUB2 gene. 1071 63

We screened for mutations that resulted in lethality when the G1 cyclin Cln2p was overexpressed throughout the cell cycle in Saccharomyces cerevisiae. Mutations in five complementation groups were found to give this phenotype, and three of the mutated genes were identified as MEC1, NUP170, and CDC14. Mutations in CDC14 may have been recovered in the screen because Cdc14p may reduce the cyclin B (Clb)-associated Cdc28 kinase activity in late mitosis, and Cln2p may normally activate Clb-Cdc28 kinase activity by related mechanisms. In agreement with the idea that cdc14 mutations elevate Clb-Cdc28 kinase activity, deletion of the gene for the Clb-Cdc28 inhibitor Sic1 caused synthetic lethality with cdc14-1, as did the deletion of HCT1, which is required for proteolysis of Clb2p. Surprisingly, deletion of the gene for the major B-type cyclin, CLB2, also caused synthetic lethality with the cdc14-1 mutation. The clb2 cdc14 strains arrested with replicated but unseparated DNA and unseparated spindle pole bodies; this phenotype is distinct from the late mitotic arrest of the sic1::TRP1 cdc14-1 and the cdc14-1 hct1::LEU2 double mutants and of the cdc14 CLN2 overexpressor. We found genetic interactions between CDC14 and the replication initiator gene CDC6, extending previous observations of interactions between the late mitotic function of Cdc14p and control of DNA replication. We also describe genetic interactions between CDC28 and CDC14.
Mol Gen Genet 2000 Feb
PMID:Mutations in CDC14 result in high sensitivity to cyclin gene dosage in Saccharomyces cerevisiae. 1073 74

The Saccharomyces cerevisiae gene YPA1 encodes a protein homologous to the phosphotyrosyl phosphatase activator, PTPA, of the mammalian protein phosphatase type 2A (PP2A). In order to examine the biological role of PTPA, we disrupted YPA1 and characterised the phenotype of the ypa1Delta mutant. Comparison of the growth rate of the wild-type strain and the ypa1Delta mutant on glucose-rich medium after nutrient depletion showed that the ypa1Delta mutant traversed the lag period more rapidly. This accelerated progression through "Start" was also observed after release from alpha-factor-induced G1 arrest as evidenced by a higher number of budding cells, a faster increase in CLN2 mRNA expression and a more rapid reactivation of Cdc28 kinase activity. This phenotype was specific for deletion of YPA1 since it was not observed when YPA2, the second PTPA gene in budding yeast was deleted. Reintroduction of YPA1 or the human PTPA cDNA in the ypa1Delta mutant suppressed this phenotype as opposed to overexpression of YPA2. Disruption of both YPA genes is lethal, since sporulation of heterozygous diploids resulted in at most three viable spores, none of them with a ypa1Delta ypa2Delta genotype. This observation indicates that YPA1 and YPA2 share some essential functions. We compared the ypa1Delta mutant phenotype with a PP2A double deletion mutant and a PP2A temperature-sensitive mutant. The PP2A-deficient yeast strain also showed accelerated progression through the G1 phase. In addition, both PP2A and ypa1Delta mutants show similar aberrant bud morphology. This would support the notion that YPA1 may act as a positive regulator of PP2A in vivo.
J Mol Biol 2000 Sep 08
PMID:The Saccharomyces cerevisiae homologue YPA1 of the mammalian phosphotyrosyl phosphatase activator of protein phosphatase 2A controls progression through the G1 phase of the yeast cell cycle. 1096 64

The neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative disorders of childhood. We have examined mRNA levels of the CLN1, CLN2, and CLN3 genes, which are associated with the infantile, late infantile, and juvenile forms of NCL in 64 different human tissues, and have grouped the results into gastrointestinal tract, central nervous system, glandular/secretory, muscle, and carcinoma tissue types. mRNA levels for CLN3 are highest in gastrointestinal tissue and are also high in glandular/secretory tissue, whereas mRNA levels for CLN1 and CLN2 do not appear to be preferentially elevated in any tissue type. The significance of extraneural expression of CLN3 is reviewed in the context of the function of the protein.
Mol Genet Metab
PMID:Neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1, CLN2, and CLN3: functional implications for CLN3. 1100 12

We have used affinity chromatography to identify proteins that interact with Nap1, a protein previously shown to play a role in mitosis. Our studies demonstrate that a highly conserved protein called Sda1 binds to Nap1 both in vitro and in vivo. Loss of Sda1 function causes cells to arrest uniformly as unbudded cells that do not increase significantly in size. Cells arrested by loss of Sda1 function have a 1N DNA content, fail to produce the G1 cyclin Cln2, and remain responsive to mating pheromone, indicating that they arrest in G1 before Start. Expression of CLN2 from a heterologous promoter in temperature-sensitive sda1 cells induces bud emergence and polarization of the actin cytoskeleton, but does not induce cell division, indicating that the sda1 cell cycle arrest phenotype is not due simply to a failure to produce the G1 cyclins. The Sda1 protein is absent from cells arrested in G0 and is expressed before Start when cells reenter the cell cycle, further suggesting that Sda1 functions before Start. Taken together, these findings reveal that Sda1 plays a critical role in G1 events. In addition, these findings suggest that Nap1 is likely to function during G1. Consistent with this, we have found that Nap1 is required for viability in cells lacking the redundant G1 cyclins Cln1 and Cln2. In contrast to a previous study, we have found no evidence that Sda1 is required for the assembly or function of the actin cytoskeleton. Further characterization of Sda1 is likely to provide important clues to the poorly understood mechanisms that control passage through G1.
Mol Biol Cell 2001 Jan
PMID:The Sda1 protein is required for passage through start. 1116 Aug 33

Moderate hyperosmotic stress on Saccharomyces cerevisiae cells produces a temporary delay at the G1 stage of the cell cycle. This is accompanied by transitory downregulation of CLN1, CLN2 and CLB5 transcript levels, although not of CLN3, which codes for the most upstream activator of the G1/S transition. Osmotic shock to cells synchronized in early G1, when Cln3 is the only cyclin present, causes a delay in cell cycle resumption. This points to Cln3 as being a key cell cycle target for osmotic stress. We have observed that osmotic shock causes downregulation of the kinase activity of Cln3-Cdc28 complexes. This is concomitant with a temporary accumulation of Cln3 protein as a result of increased stability. The effects of the osmotic stress in G1 are not suppressed in CLN3-1 cells with increased kinase activity, as the Cln3-Cdc28 activity in this mutant is still affected by the shock. Although Hog1 is not required for the observed cell cycle arrest in hyperosmotic conditions, it is necessary to resume the cell cycle at KCl concentrations higher than 0.4 M.
Mol Microbiol 2001 Feb
PMID:Osmotic stress causes a G1 cell cycle delay and downregulation of Cln3/Cdc28 activity in Saccharomyces cerevisiae. 1125 21


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