Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wild-type cells of the budding yeast Saccharbmyces cerevisiae arrest in G1 upon nutrient exhaustion. Cell cycle arrest requires the WHI2 gene since whi2 mutants continue to divide and become abnormally small as nutrients are depleted. Here we show that CLN1 and CLN2 transcript levels in a whi2 strain are higher during exponential growth, and persist longer upon starvation, than in an isogenic wild-type strain. In contrast to CLN1 and CLN2, CLN3 levels declined only at very high cell density and were unaffected by the whi2 mutation. Elevated CLN expression is sufficient to explain the whi2 phenotype since ectopic expression of CLN1 in a nutrient-depleted culture caused cells to continue dividing and interfered with the acquisition of heat resistance. These observations show that, either directly or indirectly, Whi2 negatively regulates G1 cyclin expression. Interestingly extremely high levels of Cln1 induced filamentous growth upon nutrient deprivation, suggesting a direct connection between G1 cyclin activity and morphological responses to poor nutrient conditions.
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PMID:Deregulation of CLN1 and CLN2 in the Saccharomyces cerevisiae whi2 mutant. 921 35

Juvenile neuronal ceroid lipofuscinosis or Batten disease (JNCL) is a neurodegenerative disorder characterized by blindness, seizures, cognitive decline and early death. Brain atrophy and retinitis pigmentosa ensue because of neuronal and photoreceptor apoptosis. The CLN3 gene defective in JNCL encodes a novel 438 amino acid protein. Most affected genes harbor a deletion resulting in a truncated protein. CLN3 overexpression in NT2 cells enhances growth, reverses growth inhibition induced by serum starvation and protects from apoptosis induced by vincristine, staurosporine, and etoposide but not from death caused by ceramide. CLN3 modulates endogenous and vincristine-activated ceramide, and therefore suppresses apoptosis by impacting generation of ceramide.
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PMID:CLN3 defines a novel antiapoptotic pathway operative in neurodegeneration and mediated by ceramide. 1019 Nov 18

Xbp1, a transcriptional repressor of Saccharomyces cerevisiae with homology to Swi4 and Mbp1, is induced by stress and starvation during the mitotic cycle. It is also induced late in the meiotic cycle. Using RNA differential display, we find that genes encoding three cyclins (CLN1, CLN3, and CLB2), CYS3, and SMF2 are downregulated when Xbp1 is overexpressed and that Xbp1 can bind to sequences in their promoters. During meiosis, XBP1 is highly induced and its mRNA appears at the same time as DIT1 mRNA, but its expression remains high for up to 24 h. As such, it represents a new class of meiosis-specific genes. Xbp1-deficient cells are capable of forming viable gametes, although ascus formation is delayed by several hours. Furthermore, Xbp1 target genes are normally repressed late in meiosis, and loss of XBP1 results in their derepression. Interestingly, we find that a deletion of CLN1 also reduces the efficiency of sporulation and delays the meiotic program but that sporulation in a Deltacln1 Deltaxbp1 strain is not further delayed. Thus, CLN1 may be Xbp1's primary target in meiotic cells. We hypothesize that CLN1 plays a role early in the meiotic program but must be repressed, by Xbp1, at later stages to promote efficient sporulation.
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PMID:CLN1 and its repression by Xbp1 are important for efficient sporulation in budding yeast. 1061 Dec 26

Alkalization of the medium is associated with and required for the cellular development to meiosis and sporulation in the yeast Saccharomyces cerevisiae. To elucidate the molecular mechanisms for the significance of external alkalization, we isolated mutants defective in division arrest at G1 phase under an alkaline condition. The mutants obtained had recessive alleles of SRB10 encoding the cyclin (SRB11)-dependent protein kinase that phosphorylates the CTD domain of the largest subunit of RNA polymerase II and negatively regulates the transcriptional initiation of certain genes. A delta srb11 deletion mutant showed the same cell cycle defect. When shifted to alkali, wild-type cells decreased transcript levels of G1-cyclin genes (CLN1 to CLN3) and KIN28-CCL1 (encoding another CTD kinase-cyclin pair which, in contrast, stimulates the promoter clearance and transcriptional elongation in most genes), resulting in the accumulation of G1 cells and the hypophosphorylated form of RNA polymerase II and in an increase in cell size. However, under the same conditions, a delta srb10 mutant was defective in these events, except the downregulation of CLN1 and CLN2. The delta srb10 mutation also influenced on the transcript levels of meiosis-inducing genes called IME1 and IME2: the mutation elevated the transcript level of IME1 but reduced that of IME2, resulting in partial defects in premeiotic DNA synthesis and meiosis. Overexpression of KIN28 and CCL1 in wild-type cells impaired the alkali-induced G1 arrest and the rate of meiosis and elevated the transcript levels of SRB11 and IME1. These results indicate that a transcriptional autoregulatory loop for KIN28-CCL1 and SRB10-SRB11 is important for G1 arrest and meiosis. We also found that environmental conditions for meiosis finely regulate the transcript levels of KIN28 and CCL1, such that nitrogen starvation first elevates them but subsequent alkalization of medium decreases them.
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PMID:A transcriptional autoregulatory loop for KIN28-CCL1 and SRB10-SRB11, each encoding RNA polymerase II CTD kinase-cyclin pair, stimulates the meiotic development of S. cerevisiae. 1086 6

The rapamycin-sensitive (TOR) signalling pathway in Saccharomyces cerevisiae controls growth and cell proliferation in response to nutrient availability. Rapamycin treatment causes cells to arrest growth in G1 phase. The mechanism by which the inhibition of the TOR pathway regulates cell cycle progression is not completely understood. Here we show that rapamycin causes G1 arrest by a dual mechanism that comprises downregulation of the G1-cyclins Cln1-3 and upregulation of the Cdk inhibitor protein Sic1. The increase of Sic1 level is mostly independent of the downregulation of the G1 cyclins, being unaffected by ectopic CLN2 expression, but requires Sic1 phosphorylation of Thr173, because it is lost in cells expressing Sic1(T173A). Rapamycin-mediated Sic1 upregulation involves nuclear accumulation of a more stable, non-ubiquitinated protein. Either SIC1 deletion or CLN3 overexpression results in non-cell-cycle-specific arrest upon rapamycin treatment and makes cells sensitive to a sublethal dose of rapamycin and to nutrient starvation. In conclusion, our data indicate that Sic1 is involved in rapamycin-induced G1 arrest and that deregulated entrance into S phase severely decreases the ability of a cell to cope with starvation conditions induced by nutrient depletion or which are mimicked by rapamycin treatment.
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PMID:Rapamycin-mediated G1 arrest involves regulation of the Cdk inhibitor Sic1 in Saccharomyces cerevisiae. 1730 22

Industrial yeasts, including a sake yeast Kyokai no. 7 (K7), are generally unable to sporulate. In K7 (Saccharomyces cerevisiae) cells, IME1 transcription was not induced under sporulation conditions, and K7 cells partially restored sporulation ability when transformed with a multicopy plasmid bearing IME1. However, the mechanisms of sporulation incompetence in industrial yeasts are poorly understood. We demonstrated that the deletion of the G1 cyclin CLN3, a key activator of the cell cycle, allows K7 cells to induce IME1 transcription and sporulate under sporulation conditions. In K7 cells, CLN3 mRNA and protein were not down-regulated despite sporulation conditions. Moreover, using a two-hybrid assay, we found that Ime1-Ume6 interaction was promoted in Cln3-deficient K7 cells. Thus, Cln3 is involved in the mechanism underlying sporulation incompetence by inhibiting IME1 transcription and the Ime1-Ume6 interaction. Based on these findings, we hypothesize that the absence of transmission of nutrient starvation signals to CLN3 leads to sporulation incompetence in K7 cells.
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PMID:Cln3 blocks IME1 transcription and the Ime1-Ume6 interaction to cause the sporulation incompetence in a sake yeast, Kyokai no. 7. 2054 Nov 7

Solute carriers (SLCs) are vital as they are responsible for a major part of the molecular transport over lipid bilayers. At present, there are 430 identified SLCs, of which 28 are called atypical SLCs of major facilitator superfamily (MFS) type. These are MFSD1, 2A, 2B, 3, 4A, 4B, 5, 6, 6 L, 7, 8, 9, 10, 11, 12, 13A, 14A and 14B; SV2A, SV2B and SV2C; SVOP and SVOPL; SPNS1, SPNS2 and SPNS3; and UNC93A and UNC93B1. We studied their fundamental properties, and we also included CLN3, an atypical SLC not yet belonging to any protein family (Pfam) clan, because its involvement in the same neuronal degenerative disorders as MFSD8. With phylogenetic analyses and bioinformatic sequence comparisons, the proteins were divided into 15 families, denoted atypical MFS transporter families (AMTF1-15). Hidden Markov models were used to identify orthologues from human to Drosophila melanogaster and Caenorhabditis elegans Topology predictions revealed 12 transmembrane segments (for all except CLN3), corresponding to the common MFS structure. With single-cell RNA sequencing and in situ proximity ligation assay on brain cells, co-expressions of several atypical SLCs were identified. Finally, the transcription levels of all genes were analysed in the hypothalamic N25/2 cell line after complete amino acid starvation, showing altered expression levels for several atypical SLCs.
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PMID:Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression. 2887 41

Mutations in CLN3 cause a juvenile form of neuronal ceroid lipofuscinosis (NCL). This devastating neurological disorder, commonly known as Batten disease, is currently untreatable due to a lack of understanding of the physiological role of the protein. Recently, work in the social amoeba Dictyostelium discoideum has provided valuable new insight into the function of CLN3 in the cell. More specifically, research has linked the Dictyostelium homolog (gene: cln3, protein: Cln3) to protein secretion, adhesion, and aggregation during starvation, which initiates multicellular development. In this study, we used comparative transcriptomics to explore the mechanisms underlying the aberrant response of cln3- cells to starvation. During starvation, 1153 genes were differentially expressed in cln3- cells compared to WT. Among the differentially expressed genes were homologs of other human NCL genes including TPP1/CLN2, CLN5, CTSD/CLN10, PGRN/CLN11, and CTSF/CLN13. STRING and GO term analyses revealed an enrichment of genes linked to metabolic, biosynthetic, and catalytic processes. We then coupled the findings from the RNA-seq analysis to biochemical assays, specifically showing that loss of cln3 affects the expression and activity of lysosomal enzymes, increases endo-lysosomal pH, and alters nitric oxide homeostasis. Finally, we show that cln3- cells accumulate autofluorescent storage bodies during starvation and provide evidence linking the function of Cln3 to Tpp1 and CtsD activity. In total, this study enhances our knowledge of the molecular mechanisms underlying Cln3 function in Dictyostelium.
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PMID:Comparative transcriptomics reveals mechanisms underlying cln3-deficiency phenotypes in Dictyostelium. 3077 46

The neuronal ceroid lipofuscinoses (NCLs) are a family of neurodegenerative diseases that affect people of all ages and ethnicities, yet many of the associated genes/proteins are not well characterized. Mutations in MFSD8 (major facilitator superfamily domain-containing 8) cause an infantile form of NCL referred to as CLN7 disease. In this study, we revealed the localization and binding partners of an ortholog of human MFSD8 (Mfsd8) in the social amoeba Dictyostelium discoideum. Putative lysosomal targeting motifs are conserved in Dictyostelium Mfsd8, as are several residues mutated in CLN7 disease patients. Mfsd8 tagged with GFP localizes to endocytic compartments, which includes acidic intracellular vesicles and late endosomes. We pulled-down GFP-Mfsd8 and used mass spectrometry to reveal the Mfsd8 interactome during Dictyostelium growth and starvation. Among the identified hits were the Dictyostelium ortholog of human cathepsin D (CtsD), as well as proteins linked to the functions of the CLN3 (Cln3) and CLN5 (Cln5) orthologs in Dictyostelium. To study the function of Mfsd8, we validated a publically available mfsd8- cell line (GWDI Project) and then used this knockout cell line to show that Mfsd8 influences the secretion of Cln5 and CtsD. This information is then integrated into an emerging model describing the molecular networking of NCL proteins in Dictyostelium. In total, this study identifies Dictyostelium as a new model system for studying CLN7 disease.
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PMID:Mfsd8 localizes to endocytic compartments and influences the secretion of Cln5 and cathepsin D in Dictyostelium. 3208 3