Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Saccharomyces cerevisiae cells harboring the temperature-sensitive mutation rpo21-4, in the gene encoding the largest subunit of RNA polymerase II, were shown to be partially impaired for cell-cycle progress at a permissive temperature, and to become permanently blocked at the cell-cycle regulatory step, START, at a restrictive temperature. The rpo21-4 mutation was lethal in combination with cdc28 mutations in the p34 protein kinase gene required for START. Transcripts of the CLN1 and CLN2 genes, encoding G1-cyclin proteins that, along with p34, are necessary for START, were decreased in abundance by the rpo21-4 mutation at a restrictive temperature. Increased G1-cyclin production, by expression of the CLN1 or CLN2 genes from a heterologous GAL promoter, overcame the rpo21-4-mediated START inhibition, but such mutant cells nevertheless remained unable to proliferate at a restrictive temperature. These findings reveal that START can be particularly sensitive to an impaired RNA polymerase II function, presumably through effects on G1-cyclin expression.
Mol Gen Genet 1993 Nov
PMID:An impaired RNA polymerase II activity in Saccharomyces cerevisiae causes cell-cycle inhibition at START. 824 87

For cells of the yeast Saccharomyces cerevisiae, heat shock causes a transient inhibition of the cell cycle-regulatory step START. We have determined that this heat-induced START inhibition is accompanied by decreased CLN1 and CLN2 transcript abundance and by possible posttranscriptional changes to CLN3 (WHI1/DAF1) cyclin activity. Persistent CLN2 expression from a heterologous promoter or the CLN2-1 or CLN3-1 alleles that are thought to encode cyclin proteins with increased stability eliminated heat-induced START inhibition but did not affect other aspects of the heat shock response. Heat-induced START inhibition was shown to be independent of functions that regulate cyclin activity under other conditions and of transcriptional regulation of SWI4, an activator of cyclin transcription. Cells lacking Bcy1 function and thus without cyclic AMP control of A kinase activity were inhibited for START by heat shock as long as A kinase activity was attenuated by mutation. We suggest that heat shock mediates START blockage through effects on the G1 cyclins.
Mol Cell Biol 1993 Feb
PMID:Heat shock-mediated cell cycle blockage and G1 cyclin expression in the yeast Saccharomyces cerevisiae. 838 Aug 88

We have identified two processes in the G1 phase of the Saccharomyces cerevisiae cell cycle that are required before nutritionally arrested cells are able to return to proliferative growth. The first process requires protein synthesis and is associated with increased expression of the G1 cyclin gene CLN3. This process requires nutrients but is independent of Ras and cyclic AMP (cAMP). The second process requires cAMP. This second process is rapid, is independent of protein synthesis, and produces a rapid induction of START-specific transcripts, including CLN1 and CLN2. The ability of a nutritionally arrested cell to respond to cAMP is dependent on completion of the first process, and this is delayed in cells carrying a CLN3 deletion. Mating pheromone blocks the cAMP response but does not alter the process upstream of Ras-cAMP. These results suggest a model linking the Ras-cAMP pathway with regulation of G1 cyclin expression.
Mol Cell Biol 1993 Oct
PMID:Connections between the Ras-cyclic AMP pathway and G1 cyclin expression in the budding yeast Saccharomyces cerevisiae. 841 27

Yeast cells arrest during the G1 interval of the cell cycle in response to peptide mating pheromones. The FAR1 gene is required for cell cycle arrest but not for a number of other aspects of the pheromone response. Genetic evidence suggests that FAR1 is required specifically for inactivation of the G1 cyclin CLN2. From these observations, the FAR1 gene has been proposed to encode an element of the interface between the mating pheromone signal transduction pathway and the cell cycle regulatory apparatus. We show here that FAR1 is necessary for the decrease in CLN1 and CLN2 transcript accumulation observed in response to mating pheromone but is unnecessary for regulation of the same transcripts during vegetative growth. However, the defect in regulation of CLN1 expression is dependent upon CLN2. We show that pheromone regulates the abundance of Cln2 at a posttranscriptional level and that FAR1 is required for that regulation. From these observations, we suggest that FAR1 function is limited to posttranscriptional regulation of CLN2 expression by mating pheromone. The failure of mating pheromone to repress CLN2 transcript levels in far1 mutants can be explained by the stimulatory effect of the persistent Cln2 protein on CLN2 transcription via the CLN/CDC28-dependent feedback pathway.
Mol Cell Biol 1993 Feb
PMID:FAR1 is required for posttranscriptional regulation of CLN2 gene expression in response to mating pheromone. 842 74

At a point in late G1 termed Start, yeast cells enter S phase, duplicate their spindle pole bodies, and form buds. These events require activation of Cdc28 kinase by G1 cyclins. Swi4 associates with Swi6 to form the SCB-binding factor complex which activates G1 cyclin genes CLN1 and CLN2 in late G1. In G2 and M phases, the transcriptional activity of SCB-binding factor is repressed by the mitotic Clb2/Cdc28 kinase. Mbp1, a transcription factor related to Swi4, forms the MCB-binding factor complex with Swi6, which activates DNA synthesis genes and S-phase cyclin genes CLB5 and CLB6 in late G1. Clb2/Cdc28 kinase is not required for the repression of MCB-binding factor transcriptional activity in G2 and M phase. We show here that the Swi4 carboxy terminus is sufficient for interaction with Swi6 in vitro. A carboxy-terminal domain of Swi6 is required and sufficient for interaction with Swi4. The carboxy terminus of Mbp1 is sufficient for interaction with Swi6, and the carboxy terminus of Swi6 is required for interaction with Mbp1. By coimmunoprecipitation, we show that Swi4 but not Mbp1 interacts with Clb2/Cdc28 kinase in vivo during the G2 and M phases of the cell cycle. We demonstrate that the ankyrin repeats of Swi4 mediate the interaction with Clb2/Cdc28 kinase. The ankyrin repeats constitute a domain by which a cell cycle-specific transcription factor can interact with cyclin-dependent kinase complexes, thus enabling it to link its transcriptional activity to cell cycle progression.
Mol Cell Biol 1996 Jun
PMID:The Saccharomyces cerevisiae Start-specific transcription factor Swi4 interacts through the ankyrin repeats with the mitotic Clb2/Cdc28 kinase and through its conserved carboxy terminus with Swi6. 864 72

The three budding yeast CLN genes appear to be functionally redundant for cell cycle Start: any single CLN gene is sufficient to promote Start, while the cln1 cln2 cln3 triple mutant is Start defective and inviable. Both quantitative and apparently qualitative differences between CLN genes have been reported, but available data do not in general allow distinction between qualitative functional differences as opposed to simply quantitative differences in expression or function. To determine if there are intrinsic qualitative differences between Cln proteins, we compared CLN2, CLN3, and crippled (but still partially active) CLN2 genes in a range of assays that differentiate genetically between CLN2 and CLN3. The results suggest that different potencies of Cln2, Cln3, and Cln2 mutants in functional assays cannot be accounted for by a simple quantitative model for their action, since Cln3 is at least as active as Cln2 and much more active than the Cln2 mutants in driving Swi4/Swi6 cell cycle box (SCB)-regulated transcription and cell cycle initiation in cln1 cln2 cln3 bck2 strains, but Cln3 has little or no activity in other assays in which Cln2 and the Cln2 mutants function. Differences in Cln protein abundance are unlikely to account for these results. Cln3-associated kinase is therefore likely to have an intrinsic in vivo substrate specificity distinct from that of Cln2-associated kinase, despite their functional redundancy. Consistent with the idea that Cln3 may be the primary transcriptional activator of CLN1, CLN2, and other genes, the activation of CLN2 transcription was found to be sensitive to the gene dosage of CLN3 but not to the gene dosage of CLN2.
Mol Cell Biol 1996 Dec
PMID:Saccharomyces cerevisiae G1 cyclins differ in their intrinsic functional specificities. 894 34

The storage of subunit c of mitochondrial ATP synthase, other hydrophobic peptides, and autofluorescent pigment in both late infantile (CLN2) and juvenile (CLN3) neuronal ceroid lipofuscinosis, but not in infantile (CLN1), has raised the question of abnormal mitochondrial function. We now report a partial deficiency in three types of fatty acid oxidation in intact skin fibroblasts from CLN2 and CLN3 patients, but not CLN1. We observed a statistically significant 33% reduction in palmitate (beta-oxidation; mainly mitochondrial) and lignocerate (beta-oxidation; mainly peroxisomal), and a 50% reduction in phytanic acid (alpha-oxidation; mainly peroxisomal) in the absence of exogenous carnitine. In contrast, when we measured fatty acid beta-oxidation (lignoceric acid and palmitic acid), in the same human skin fibroblasts, following lysis in the presence of carnitine, we found no difference in enzyme activity among normal, CLN1, CLN2, and CLN3. However, we did observe a 40% reduction in peroxisomal particulate (bound) catalase activity in CLN1 and CLN2 fibroblasts, which typically results from organellar lipid accumulation or a membrane abnormality. However, total catalase levels were normal, and Western blot analysis of this and three other major oxidant protective enzymes (Mn-dependent superoxide dismutase [MnSOD], CuZn-dependent superoxide dismutase [CuZnSOD], and glutathione peroxidase) were normal in CLN1, CLN2, and CLN3, as well as in liver from an animal (English Setter dog) model for CLN, which shows similar pathology and subunit c storage. Our data showing differences between CLN1 and forms CLN2 and CLN3 suggest some type of mitochondrial membrane abnormality as the source of the pathology in CLN2 and CLN3.
Mol Chem Neuropathol
PMID:Mitochondrial abnormalities in CLN2 and CLN3 forms of Batten disease. 897 98

The childhood neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurones and other cells. Three main subtypes have been identified according to age of onset, clinical features and ultrastructural morphology. These are infantile NCL (INCL; CLN1), classical late infantile NCL (LINCL; CLN2) and juvenile NCL (JNCL; CLN3). Several atypical forms of late infantile NCL (LINCL) have also been described including a Finnish variant LINCL (CLN5). The CLN2 gene has been excluded from the CLN1, CLN3 and CLN5 loci. A genome search was initiated using a homozygosity mapping strategy in five classical LINCL and two variant LINCL consanguineous families. A common region of homozygosity was identified on chromosome 11p15 in two of the classical families. Analysis of a further 33 classical LINCL families supported linkage in this region (Zmax = 3.07 at theta = 0.06 at D11S1338). A common region of homozygosity was also observed on chromosome 15q21-23 in the two variant LINCL families. Extension of the analysis to include a further seven families of identical ultrastructural phenotype established linkage to this region (Zmax = 6.00 at theta = 0.00 at D15S1020).
Hum Mol Genet 1997 Apr
PMID:Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21-23. 909 64

We have generated 50 new alleles of the yeast CLN2 gene by using site-directed mutagenesis. With the recently obtained crystal structure of cyclin A as a guide, a peptide linker sequence was inserted at 13 sites within the cyclin box of Cln2 to determine if the architecture of Cln2 is similar to that of cyclin A. Linkers inserted in what are predicted to be helices 1, 2, 3, and 5 of the cyclin box resulted in nonfunctional Cln2 molecules. Linkers inserted between these putative helix sites and in the region believed to contain a fourth helix did not have significant effects upon Cln2 function. A series of deletions in the region between the third and fifth helices indicate that the putative fourth helix may lie at the C-terminal end of this region yet is not essential for function. Two residues that are predicted to form a buried salt bridge important for interaction of two helices of the cyclin box were also mutated, and an additional set of 31 mutant alleles was generated by clustered-charge-to-alanine scanning mutagenesis. All of the mutant CLN2 alleles made in this study were tested in a variety of genetic and functional assays previously demonstrated to differentiate specific cyclin functions. Some alleles demonstrated restricted patterns of defects, suggesting that these mutations may interfere with specific aspects of Cln2 function.
Mol Cell Biol 1997 Aug
PMID:Structure-function analysis of the Saccharomyces cerevisiae G1 cyclin Cln2. 923 22

Yeasts have three functionally redundant G1 cyclins required for cell cycle progression through G1. Mutations in GIN4 and CLA4 were isolated in a screen for mutants that are inviable with deletions in the G1 cyclins CLN1 and CLN2. cln1 cln2 cla4 and cln1 cln2 gin4 cells arrest with a cytokinesis defect; this defect was efficiently rescued by CLN1 or CLN2 expression. GIN4 encodes a protein with strong homology to the Snflp serine/threonine kinase. Cla4p is homologous to mammalian p21-activated kinases (PAKs) (kinases activated by the rho-class GTPase Rac or Cdc42). We developed a kinase assay for Cla4p. Cla4p kinase was activated in vivo by the GTP-bound form of Cdc42p. The specific activity of Cla4p was cell cycle regulated, peaking near mitosis. Deletion of the Cla4p pleckstrin domain diminished kinase activity nearly threefold and eliminated in vivo activity. Deletion of the Cla4p Cdc42-binding domain increased kinase activity nearly threefold, but the mutant only weakly rescued cla4 function in vivo. This suggests that kinase activity alone is not sufficient for full function in vivo. Deletion of the Cdc42-binding domain also altered the cell cycle regulation of kinase activity. Instead of peaking at mitosis, the mutant kinase activity exhibited reduced cell cycle regulation and peaked at the G1/S border. Cla4p kinase activity was not reduced by mutational inactivation of gin4, suggesting that Gin4p may be downstream or parallel to Cla4p in the regulation of cytokinesis.
Mol Cell Biol 1997 Sep
PMID:Cla4p, a Saccharomyces cerevisiae Cdc42p-activated kinase involved in cytokinesis, is activated at mitosis. 927 84


<< Previous 1 2 3 4 5 6 7 8 Next >>