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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The G1 cyclin Cln2 negatively regulates the mating-factor pathway. In a genetic screen to identify factors required for this regulation, we identified an allele of CDC28 (cdc28-csr1) that blocked this function of Cln2. Cln2 immunoprecipitated from cdc28-csr1 cells was completely defective in histone H1 kinase activity, due to defects in Cdc28 binding and activation by Cln2. In contrast, Clb2-associated H1 kinase and Cdc28 binding was normal in immunoprecipitates from these cells. cdc28-csr1 was significantly deficient in other aspects of genetic interaction with Cln2. The cdc28-csr1 mutation was determined to be Q188P, in the T loop distal to most of the probable Cdk-cyclin interaction regions. We performed random mutagenesis of CDC28 to identify additional alleles incapable of causing CLN2-dependent mating-factor resistance but capable of complementing cdc28 temperature-sensitive and null alleles. Two such mutants had highly defective Cln2-associated kinase, but, surprisingly, two other mutants had levels of Cln2-associated kinase near to wild-type levels. We performed a complementary screen for CDC28 mutants that could cause efficient Cln2-dependent mating-factor resistance but not complement a cdc28 null allele. Most such mutants were found to alter residues essential for kinase activity; the proteins had little or no associated kinase activity in bulk or in association with Cln2. Several of these mutants also functioned in another assay for CLN2-dependent function not involving the mating-factor pathway, complementing the temperature sensitivity of a cln1 cln3 cdc28-csr1 strain. These results could indicate that Cln2-Cdc28 kinase activity is not directly relevant to some CLN2-mediated functions. Mutants of this sort should be useful in differentiating the function of Cdc28 complexed with different cyclin regulatory subunits.
Mol Cell Biol 1998 Jan
PMID:Isolation and characterization of new alleles of the cyclin-dependent kinase gene CDC28 with cyclin-specific functional and biochemical defects. 941 76

The Saccharomyces cerevisiae cell cycle is arrested in G1 phase by the mating factor pathway. Genetic evidence has suggested that the G1 cyclins Cln1, Cln2, and Cln3 are targets of this pathway whose inhibition results in G1 arrest. Inhibition of Cln1- and Cln2-associated kinase activity by the mating factor pathway acting through Far1 has been described. Here we report that Cln3-associated kinase activity is inhibited by mating factor treatment, with dose response and timing consistent with involvement in cell cycle arrest. No regulation of Cln3-associated kinase was observed in a fus3 kss1 strain deficient in mating factor pathway mitogen-activated protein (MAP) kinases. Inhibition occurs mainly at the level of specific activity of Cln3-Cdc28 complexes. Inhibition of the C-terminally truncated Cln3-1-associated kinase is not observed; such truncations were previously identified genetically as causing resistance to mating factor-induced cell cycle arrest. Regulation of Cln3-associated kinase specific activity by mating factor treatment requires Far1. Overexpression of Far1 restores inhibition of C-terminally truncated Cln3-1-associated kinase activity. G2/M-arrested cells are unable to regulate Cln3-associated kinase, possibly because of cell cycle regulation of Far1 abundance. Inhibition of Cln3-associated kinase activity by the mating factor pathway may allow this pathway to block the earliest step in normal cell cycle initiation, since Cln3 functions as the most upstream G1-acting cyclin, activating transcription of the G1 cyclins CLN1 and CLN2 as well as of the S-phase cyclins CLB5 and CLB6.
Mol Cell Biol 1998 Jan
PMID:Cln3-associated kinase activity in Saccharomyces cerevisiae is regulated by the mating factor pathway. 941 90

Yeast cells are keenly sensitive to the availability and quality of nutrients. Addition of glucose to cells growing on a poorer carbon source elicits a cell cycle delay during G1 phase and a concomitant increase in the cell size. The signal is transduced through the RAS-cyclic AMP pathway. Using synchronized populations of G1 cells, we show that the increase in cell size required for budding depends upon CLN1 but not other G1 cyclins. This delay in cell cycle initiation is associated specifically with transcriptional repression of CLN1. CLN2 is not repressed. Repression of CLN1 is not limited to the first cycle following glucose addition but occurs in each cell cycle during growth on glucose. A 106-bp fragment of the CLN1 promoter containing the three MluI cell cycle box (MCB) core elements responsible for the majority of CLN1-associated upstream activation sequence activity is sufficient to confer glucose-induced repression on a heterologous reporter. A mutant CLN2 promoter that is rendered dependent upon its three MCB core elements due to inactivation of its Swi4-dependent cell cycle box (SCB) elements is also repressed by glucose. The response to glucose is partially suppressed by inactivation of SWI4, but not MBP1, which is consistent with the dependence of MCB core elements upon the SCB-binding transcription factor (SBF). We suggest that differential regulation of CLN1 and CLN2 by glucose results from differences in the capacity of SBF to activate transcription driven by SCB and MCB core elements. Finally, we show that transcriptional repression is sufficient to explain the cell cycle delay that occurs in response to glucose.
Mol Cell Biol 1998 May
PMID:Regulation of cell size by glucose is exerted via repression of the CLN1 promoter. 956 70

The gene coding for human cyclin K was isolated as a CPR (cell-cycle progression restoration) gene by virtue of its ability to impart a Far- phenotype to the budding yeast Saccharomyces cerevisiae and to rescue the lethality of a deletion of the G1 cyclin genes CLN1, CLN2, and CLN3. The cyclin K gene encodes a 357-amino-acid protein most closely related to human cyclins C and H, which have been proposed to play a role in regulating basal transcription through their association with and activation of cyclin-dependent kinases (Cdks) that phosphorylate the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II). Murine and Drosophila melanogaster homologs of cyclin K have also been identified. Cyclin K mRNA is ubiquitously expressed in adult mouse and human tissues, but is most abundant in the developing germ cells of the adult testis and ovaries. Cyclin K is associated with potent CTD kinase and Cdk kinase (CAK) activity in vitro and coimmunoprecipitates with the large subunit of RNAP II. Thus, cyclin K represents a new member of the "transcription" cyclin family which may play a dual role in regulating Cdk and RNAP II activity.
Mol Cell Biol 1998 Jul
PMID:Human cyclin K, a novel RNA polymerase II-associated cyclin possessing both carboxy-terminal domain kinase and Cdk-activating kinase activity. 963 13

In the yeast Saccharomyces cerevisiae, Sic1, an inhibitor of Clb-Cdc28 kinases, must be phosphorylated and degraded in G1 for cells to initiate DNA replication, and Cln-Cdc28 kinase appears to be primarily responsible for phosphorylation of Sic1. The Pho85 kinase is a yeast cyclin-dependent kinase (Cdk), which is not essential for cell growth unless both CLN1 and CLN2 are absent. We demonstrate that Pho85, when complexed with Pcl1, a G1 cyclin homologue, can phosphorylate Sic1 in vitro, and that Sic1 appears to be more stable in pho85Delta cells. Three consensus Cdk phosphorylation sites present in Sic1 are phosphorylated in vivo, and two of them are required for prompt degradation of the inhibitor. Pho85 and other G1 Cdks appear to phosphorylate Sic1 at different sites in vivo. Thus at least two distinct Cdks can participate in phosphorylation of Sic1 and may therefore regulate progression through G1.
Mol Biol Cell 1998 Sep
PMID:Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation. 972 2

This study describes the phenotype/genotype analyses of 56 probands with a juvenile onset, some of which had atypical features of neuronal ceroid lipofuscinosis, collected at the New York State Institute for Basic Research (IBR). In this group, we found probands with abundant curvilinear profiles in lysosomal storage material, deficiency of pepstatin-insensitive peptidase, and mutations in the CLN2 gene, as well as patients with a predominance of granular osmiophilic deposits in the lysosomal storage material, deficiency of palmitoyl-protein thioesterase, and mutations in the CLN1 gene. We have divided the probands into two categories: typical (or classic) and atypical. Most of the typical and atypical probands had onset of symptoms about or after 4 years of age. Interfamiliar and intrafamiliar variations were found, especially in the speed of becoming practically blind. Thus, our study indicates that some mutations in the CLN1, CLN2, and CLN3 genes may be associated with late onset of the disease process, may have a more benign clinical course, and clinic overlap with other forms of neuronal ceroid lipofuscinosis.
Mol Genet Metab 1999 Apr
PMID:Reevaluation of neuronal ceroid lipofuscinoses: atypical juvenile onset may be the result of CLN2 mutations. 1019 Nov 10

Marked clinical heterogeneity is seen in the late-infantile subtype of NCL (LINCL), complicating genetic analysis. In addition to the classical subtype, encoded by CLN2 on chromosome 11p15.5, several variant subtypes have also been described. In this paper, we report our progress in cloning a variant LINCL gene mapped in a small group of Costa Rican families. Clinically, these patients appear similar to classical LINCL patients, except onset of the disease is delayed and the course is milder. Extended haplotype analysis confirms the localization of this gene to chromosome 15q21-22, where CLN6 has also been mapped. Using now-standard positional cloning techniques, we have developed a physical map of our candidate region. These clones have been used to order genetic markers, STSs, and ESTs in this region and will be used for the identification of the disease gene transcript.
Mol Genet Metab 1999 Apr
PMID:Progress toward the cloning of CLN6, the gene underlying a variant LINCL. 1019 Nov 24

An overview of patients in the Netherlands who are known to us with neuronal ceroid lipofuscinosis (NCL) is presented. Several CLN genes involved in NCL have been isolated or mapped. We have analyzed families with different types of NCL with polymorphic markers linked to CLN loci to investigate the genetic heterogeneity of NCL in the Netherlands. Haplotype analysis suggests that in addition to the CLN2 and CLN6 genes another gene is involved in at least one family with late infantile NCL in the Netherlands. The CLN2 and CLN6 loci have also been excluded in a family with protracted juvenile NCL.
Mol Genet Metab 1999 Apr
PMID:Genetic heterogeneity of neuronal ceroid lipofuscinosis in The Netherlands. 1019 Nov 26

Several neuronal ceroid lipofuscinoses (NCL) show storage of subunit c of mitochondrial ATP synthase. The neurodegenerative process, however, remains obscure. We previously reported a decreased basal ATP synthase activity in fibroblasts from late-infantile NCL (CLN2) and juvenile NCL (CLN3) patients. We have now extended the study of the ATP synthase system to an ovine NCL (a model for the late-infantile NCL variant, CLN6) and the infantile NCL (CLN1). In fibroblasts from healthy sheep, active regulation of ATP synthase in response to cellular energy demand was present similar to human cells: ATP synthase was down-regulated under conditions of anoxia or functional uncoupling and was up-regulated in response to calcium. In fibroblasts from NCL sheep, basal ATP synthase activity was slightly elevated and down-regulation in response to anoxia or uncoupling of mitochondria also occurred. Calcium produced an unexpected down-regulation to 55% of basal activity. Activities of respiratory chain enzymes did not differ between healthy and NCL sheep. In fibroblasts from CLN1 patients, basal ATP synthase activity was reduced and regulation of the enzyme was absent. Activities of respiratory chain complexes II and IV were reduced. The defect of ATP synthase regulation found in fibroblasts from NCL sheep and infantile NCL patients is different from the ATP synthase deficiencies demonstrated in late-infantile and juvenile NCL, but problems of mitochondrial energy production, if also expressed in brain, would be a common feature of several NCL forms. Deficient ATP supply could result in degeneration of neurons, especially in those with high energy requirements.
Mol Genet Metab 1999 Apr
PMID:Anomalies of mitochondrial ATP synthase regulation in four different types of neuronal ceroid lipofuscinosis. 1019 Nov 28

Candida albicans undergoes a dramatic morphological transition in response to various growth conditions. This ability to switch from a yeast form to a hyphal form is required for its pathogenicity. The intractability of Candida to traditional genetic approaches has hampered the study of the molecular mechanism governing this developmental switch. Our approach is to use the more genetically tractable yeast Saccharomyces cerevisiae to yield clues about the molecular control of filamentation for further studies in Candida. G1 cyclins Cln1 and Cln2 have been implicated in the control of morphogenesis in S. cerevisiae. We show that C. albicans CLN1 (CaCLN1) has the same cell cycle-specific expression pattern as CLN1 and CLN2 of S. cerevisiae. To investigate whether G1 cyclins are similarly involved in the regulation of cell morphogenesis during the yeast-to-hypha transition of C. albicans, we mutated CaCLN1. Cacln1/Cacln1 cells were found to be slower than wild-type cells in cell cycle progression. The Cacln1/Cacln1 mutants were also defective in hyphal colony formation on several solid media. Furthermore, while mutant strains developed germ tubes under several hypha-inducing conditions, they were unable to maintain the hyphal growth mode in a synthetic hypha-inducing liquid medium and were deficient in the expression of hypha-specific genes in this medium. Our results suggest that CaCln1 may coordinately regulate hyphal development with signal transduction pathways in response to various environmental cues.
Mol Cell Biol 1999 Jun
PMID:A G1 cyclin is necessary for maintenance of filamentous growth in Candida albicans. 1033 Jan 42


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