Journal articles: 'CLN6'

1

Levine, K., K. Huang, and F. R. Cross. "Saccharomyces cerevisiae G1 cyclins differ in their intrinsic functional specificities." Molecular and Cellular Biology 16, no. 12 (December 1996): 6794–803. http://dx.doi.org/10.1128/mcb.16.12.6794.

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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.

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2

Epstein, C. B., and F. R. Cross. "Genes that can bypass the CLN requirement for Saccharomyces cerevisiae cell cycle START." Molecular and Cellular Biology 14, no. 3 (March 1994): 2041–47. http://dx.doi.org/10.1128/mcb.14.3.2041-2047.1994.

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Cell cycle START in Saccharomyces cerevisiae requires at least one of the three CLN genes (CLN1, CLN2, or CLN3). A total of 12 mutations bypassing this requirement were found to be dominant mutations in a single gene that we named BYC1 (for bypass of CLN requirement). We also isolated a plasmid that had cln bypass activity at a low copy number; the gene responsible was distinct from BYC1 and was identical to the recently described BCK2 gene. Strains carrying bck2::ARG4 disruption alleles were fully viable, but bck2::ARG4 completely suppressed the cln bypass activity of BYC1. swi4 and swi6 deletion alleles also efficiently suppressed BYC1 cln bypass activity; Swi4 and Swi6 are components of a transcription factor previously implicated in control of CLN1 and CLN2 expression. bck2::ARG4 was synthetically lethal with cln3 deletion, suggesting that CLN1 and CLN2 cannot function in the simultaneous absence of BCK2 and CLN3; this observation correlates with low expression of CLN1 and CLN2 in bck2 strains deprived of CLN3 function. Thus, factors implicated in CLN1 and CLN2 expression and/or function are also required for BYC1 function in the absence of all three CLN genes; this may suggest the involvement of other targets of Swi4, Swi6, and Bck2 in START.

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3

Epstein, C. B., and F. R. Cross. "Genes that can bypass the CLN requirement for Saccharomyces cerevisiae cell cycle START." Molecular and Cellular Biology 14, no. 3 (March 1994): 2041–47. http://dx.doi.org/10.1128/mcb.14.3.2041.

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Cell cycle START in Saccharomyces cerevisiae requires at least one of the three CLN genes (CLN1, CLN2, or CLN3). A total of 12 mutations bypassing this requirement were found to be dominant mutations in a single gene that we named BYC1 (for bypass of CLN requirement). We also isolated a plasmid that had cln bypass activity at a low copy number; the gene responsible was distinct from BYC1 and was identical to the recently described BCK2 gene. Strains carrying bck2::ARG4 disruption alleles were fully viable, but bck2::ARG4 completely suppressed the cln bypass activity of BYC1. swi4 and swi6 deletion alleles also efficiently suppressed BYC1 cln bypass activity; Swi4 and Swi6 are components of a transcription factor previously implicated in control of CLN1 and CLN2 expression. bck2::ARG4 was synthetically lethal with cln3 deletion, suggesting that CLN1 and CLN2 cannot function in the simultaneous absence of BCK2 and CLN3; this observation correlates with low expression of CLN1 and CLN2 in bck2 strains deprived of CLN3 function. Thus, factors implicated in CLN1 and CLN2 expression and/or function are also required for BYC1 function in the absence of all three CLN genes; this may suggest the involvement of other targets of Swi4, Swi6, and Bck2 in START.

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4

Vallen, E. A., and F. R. Cross. "Mutations in RAD27 define a potential link between G1 cyclins and DNA replication." Molecular and Cellular Biology 15, no. 8 (August 1995): 4291–302. http://dx.doi.org/10.1128/mcb.15.8.4291.

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The yeast Saccharomyces cerevisiae has three G1 cyclin (CLN) genes with overlapping functions. To analyze the functions of the various CLN genes, we examined mutations that result in lethality in conjunction with loss of cln1 and cln2. We have isolated alleles of RAD27/ERC11/YKL510, the yeast homolog of the gene encoding flap endonuclease 1, FEN-1.cln1 cln2 rad27/erc11 cells arrest in S phase; this cell cycle arrest is suppressed by the expression of CLN1 or CLN2 but not by that of CLN3 or the hyperactive CLN3-2. rad27/erc11 mutants are also defective in DNA damage repair, as determined by their increased sensitivity to a DNA-damaging agent, increased mitotic recombination rates, and increased spontaneous mutation rates. Unlike the block in cell cycle progression, these phenotypes are not suppressed by CLN1 or CLN2. CLN1 and CLN2 may activate an RAD27/ERC11-independent pathway specific for DNA synthesis that CLN3 is incapable of activating. Alternatively, CLN1 and CLN2 may be capable of overriding a checkpoint response which otherwise causes cln1 cln2 rad27/erc11 cells to arrest. These results imply that CLN1 and CLN2 have a role in the regulation of DNA replication. Consistent with this, GAL-CLN1 expression in checkpoint-deficient, mec1-1 mutant cells results in both cell death and increased chromosome loss among survivors, suggesting that CLN1 overexpression either activates defective DNA replication or leads to insensitivity to DNA damage.

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5

Cross, F. R. "Cell cycle arrest caused by CLN gene deficiency in Saccharomyces cerevisiae resembles START-I arrest and is independent of the mating-pheromone signalling pathway." Molecular and Cellular Biology 10, no. 12 (December 1990): 6482–90. http://dx.doi.org/10.1128/mcb.10.12.6482-6490.1990.

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Null mutations in three genes encoding cyclin-like proteins (CLN1, CLN2, and CLN3) in Saccharomyces cerevisiae cause cell cycle arrest in G1 (cln arrest). In cln1 cln2 cln3 strains bearing plasmids containing the CLN3 (also called WHI1 or DAF1) coding sequence under the transcriptional control of a galactose-regulated promoter, shift from galactose to glucose medium (shutting off synthesis of CLN3 mRNA) allowed completion of cell cycles in progress but caused arrest in the ensuing unbudded G1 phase. Cell growth was not inhibited in arrested cells. Cell division occurred in glucose medium even if cells were arrested in S phase during the initial 2 h of glucose treatment, suggesting that CLN function may not be required in the cell cycle after S phase. However, when the coding sequence of the hyperactive C-terminal truncation allele CLN3-2 (formerly DAF1-1) was placed under GAL control, cells went through multiple cycles before arresting after a shift from galactose to glucose. These results suggest that the C terminus of the wild-type protein confers functional instability. cln-arrested cells are mating competent. However, cln arrest is distinct from constitutive activation of the mating-factor signalling pathway because cln-arrested cells were dependent on the addition of pheromone both for mating and for induction of an alpha-factor-induced transcript, FUS1, and because MATa/MAT alpha (pheromone-nonresponsive) strains were capable of cln arrest in G1 (although a residual capacity for cell division before arrest was observed in MATa/MAT alpha strains). These results are consistent with a specific CLN requirement for START transit.

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6

Cross, F. R. "Cell cycle arrest caused by CLN gene deficiency in Saccharomyces cerevisiae resembles START-I arrest and is independent of the mating-pheromone signalling pathway." Molecular and Cellular Biology 10, no. 12 (December 1990): 6482–90. http://dx.doi.org/10.1128/mcb.10.12.6482.

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Null mutations in three genes encoding cyclin-like proteins (CLN1, CLN2, and CLN3) in Saccharomyces cerevisiae cause cell cycle arrest in G1 (cln arrest). In cln1 cln2 cln3 strains bearing plasmids containing the CLN3 (also called WHI1 or DAF1) coding sequence under the transcriptional control of a galactose-regulated promoter, shift from galactose to glucose medium (shutting off synthesis of CLN3 mRNA) allowed completion of cell cycles in progress but caused arrest in the ensuing unbudded G1 phase. Cell growth was not inhibited in arrested cells. Cell division occurred in glucose medium even if cells were arrested in S phase during the initial 2 h of glucose treatment, suggesting that CLN function may not be required in the cell cycle after S phase. However, when the coding sequence of the hyperactive C-terminal truncation allele CLN3-2 (formerly DAF1-1) was placed under GAL control, cells went through multiple cycles before arresting after a shift from galactose to glucose. These results suggest that the C terminus of the wild-type protein confers functional instability. cln-arrested cells are mating competent. However, cln arrest is distinct from constitutive activation of the mating-factor signalling pathway because cln-arrested cells were dependent on the addition of pheromone both for mating and for induction of an alpha-factor-induced transcript, FUS1, and because MATa/MAT alpha (pheromone-nonresponsive) strains were capable of cln arrest in G1 (although a residual capacity for cell division before arrest was observed in MATa/MAT alpha strains). These results are consistent with a specific CLN requirement for START transit.

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7

Jeoung, Doo-Il, L. J. W. M. Oehlen, and Frederick R. Cross. "Cln3-Associated Kinase Activity inSaccharomyces cerevisiae Is Regulated by the Mating Factor Pathway." Molecular and Cellular Biology 18, no. 1 (January 1, 1998): 433–41. http://dx.doi.org/10.1128/mcb.18.1.433.

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ABSTRACT 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.

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8

Vesa, Jouni, Mark H. Chin, Kathrin Oelgeschläger, Juha Isosomppi, Esteban C. DellAngelica, Anu Jalanko, and Leena Peltonen. "Neuronal Ceroid Lipofuscinoses Are Connected at Molecular Level: Interaction of CLN5 Protein with CLN2 and CLN3." Molecular Biology of the Cell 13, no. 7 (July 2002): 2410–20. http://dx.doi.org/10.1091/mbc.e02-01-0031.

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Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative storage diseases characterized by mental retardation, visual failure, and brain atrophy as well as accumulation of storage material in multiple cell types. The diseases are caused by mutations in the ubiquitously expressed genes, of which six are known. Herein, we report that three NCL disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins based on coimmunoprecipitation and in vitro binding assays. Furthermore, disease mutations in CLN5 abolished interaction with CLN2, while not affecting association with CLN3. The molecular characterization of CLN5 revealed that it was synthesized as four precursor forms, due to usage of alternative initiator methionines in translation. All forms were targeted to lysosomes and the longest form, translated from the first potential methionine, was associated with membranes. Interactions between CLN polypeptides were shown to occur with this longest, membrane-bound form of CLN5. Both intracellular targeting and posttranslational glycosylation of the polypeptides carrying human disease mutations were similar to wild-type CLN5.

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9

Di Como, C. J., H. Chang, and K. T. Arndt. "Activation of CLN1 and CLN2 G1 cyclin gene expression by BCK2." Molecular and Cellular Biology 15, no. 4 (April 1995): 1835–46. http://dx.doi.org/10.1128/mcb.15.4.1835.

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The Saccharomyces cerevisiae CLN3 protein, a G1 cyclin, positively regulates the expression of CLN1 and CLN2, two additional G1 cyclins whose expression during late G1 is activated, in part, by the transcription factors SWI4 and SWI6. We isolated 12 complementation groups of mutants that require CLN3. The members of one of these complementation groups have mutations in the BCK2 gene. In a wild-type CLN3 genetic background, bck2 mutants have a normal growth rate but have a larger cell size, are more sensitive to alpha-factor, and have a modest defect in the accumulation of CLN1 and CLN2 RNA. In the absence of CLN3, bck2 mutations cause an extremely slow growth rate: the cells accumulate in late G1 with very low levels of CLN1 and CLN2 RNA. The slow growth rate and long G1 delay of bck2 cln3 mutants are cured by heterologous expression of CLN2. Moreover, overexpression of BCK2 induces very high levels of CLN1, CLN2, and HCS26 RNAs. The results suggest that BCK2 and CLN3 provide parallel activation pathways for the expression of CLN1 and CLN2 during late G1.

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10

HEINE, Claudia, Jaana TYYNELÄ, Jonathan D. COOPER, David N. PALMER, Milan ELLEDER, Alfried KOHLSCHÜTTER, and Thomas BRAULKE. "Enhanced expression of manganese-dependent superoxide dismutase in human and sheep CLN6 tissues." Biochemical Journal 376, no. 2 (December 1, 2003): 369–76. http://dx.doi.org/10.1042/bj20030598.

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Neuronal ceroid lipofuscinosis type 6 and its sheep model (OCL6) are lysosomal storage disorders caused by mutations in the CLN6 gene product of unknown function. It has been proposed that mitochondrial dysfunction, including defects in mitochondrial protein degradation, organelle enlargement and functional changes in oxidative phosphorylation, may contribute to the disease pathology. To further explore the disease mechanisms underlying CLN6, protein expression was compared between normal and affected tissues. Using two-dimensional electrophoretic separation of proteins, MS and immunoblotting, MnSOD (manganese-dependent superoxide dismutase) was found to be significantly and specifically increased in fibroblasts and brain extracts of both human and sheep affected with CLN6. Both the activity and expression of MnSOD mRNA were enhanced in affected fibroblasts. Confocal fluorescence microscopy and immunohistochemical studies revealed the presence of MnSOD in mitochondria of CLN6 fibroblasts and in CLN6 brain sections within both neurons and hypertrophic astrocytes. These data suggest that oxidative stress and/or the production of pro-inflammatory cytokines are characteristic features of human and sheep CLN6, resulting in elevated expression of MnSOD, which may be important for diagnostic purposes.

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11

Stuart, D., and C. Wittenberg. "Cell cycle-dependent transcription of CLN2 is conferred by multiple distinct cis-acting regulatory elements." Molecular and Cellular Biology 14, no. 7 (July 1994): 4788–801. http://dx.doi.org/10.1128/mcb.14.7.4788-4801.1994.

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The budding yeast Saccharomyces cerevisiae CLN1, CLN2, and CLN3 genes encode functionally redundant G1 cyclins required for cell cycle initiation. CLN1 and CLN2 mRNAs accumulate periodically throughout the cell cycle, peaking in late G1. We show that cell cycle-dependent fluctuation in CLN2 mRNA is regulated at the level of transcriptional initiation. Mutational analysis of the CLN2 promoter revealed that the major cell cycle-dependent upstream activating sequence (UAS) resides within a 100-bp fragment. This UAS contains three putative SWI4-dependent cell cycle boxes (SCBs) and two putative MluI cell cycle boxes (MCBs). Mutational inactivation of these elements substantially decreased CLN2 promoter activity but failed to eliminate periodic transcription. Similarly, inactivation of SWI4 decreased CLN2 transcription without affecting its periodicity. We have identified a second UAS in the CLN2 upstream region that can promote cell cycle-dependent transcription with kinetics similar to that of the intact CLN2 promoter. Unlike the major CLN2 UAS, this newly identified UAS promotes transcription in cells arrested in G1 by inactivation of cdc28. This novel UAS is both necessary and sufficient for regulated transcription driven by a CLN2 promoter lacking functional SCBs and MCBs. Although this UAS itself contains no SCBs or MCBs, its activity is dependent upon SWI4 function. The characteristics of this novel UAS suggest that it might have a role in initiating CLN2 expression early in G1 to activate the positive feedback loop that drives maximal Cln accumulation.

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12

Stuart, D., and C. Wittenberg. "Cell cycle-dependent transcription of CLN2 is conferred by multiple distinct cis-acting regulatory elements." Molecular and Cellular Biology 14, no. 7 (July 1994): 4788–801. http://dx.doi.org/10.1128/mcb.14.7.4788.

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The budding yeast Saccharomyces cerevisiae CLN1, CLN2, and CLN3 genes encode functionally redundant G1 cyclins required for cell cycle initiation. CLN1 and CLN2 mRNAs accumulate periodically throughout the cell cycle, peaking in late G1. We show that cell cycle-dependent fluctuation in CLN2 mRNA is regulated at the level of transcriptional initiation. Mutational analysis of the CLN2 promoter revealed that the major cell cycle-dependent upstream activating sequence (UAS) resides within a 100-bp fragment. This UAS contains three putative SWI4-dependent cell cycle boxes (SCBs) and two putative MluI cell cycle boxes (MCBs). Mutational inactivation of these elements substantially decreased CLN2 promoter activity but failed to eliminate periodic transcription. Similarly, inactivation of SWI4 decreased CLN2 transcription without affecting its periodicity. We have identified a second UAS in the CLN2 upstream region that can promote cell cycle-dependent transcription with kinetics similar to that of the intact CLN2 promoter. Unlike the major CLN2 UAS, this newly identified UAS promotes transcription in cells arrested in G1 by inactivation of cdc28. This novel UAS is both necessary and sufficient for regulated transcription driven by a CLN2 promoter lacking functional SCBs and MCBs. Although this UAS itself contains no SCBs or MCBs, its activity is dependent upon SWI4 function. The characteristics of this novel UAS suggest that it might have a role in initiating CLN2 expression early in G1 to activate the positive feedback loop that drives maximal Cln accumulation.

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13

kleine Holthaus, Sophia-Martha, Saul Herranz-Martin, Giulia Massaro, Mikel Aristorena, Justin Hoke, Michael P. Hughes, Ryea Maswood, et al. "Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease." Human Molecular Genetics 28, no. 23 (September 6, 2019): 3867–79. http://dx.doi.org/10.1093/hmg/ddz210.

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Abstract The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

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Russell, Katharina N., Nadia L. Mitchell, Martin P. Wellby, Graham K. Barrell, and David N. Palmer. "Electroretinography data from ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses." Data in Brief 37 (August 2021): 107188. http://dx.doi.org/10.1016/j.dib.2021.107188.

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15

Katz, Martin L., Reuben M. Buckley, Vanessa Biegen, Dennis P. O’Brien, Gayle C. Johnson, Wesley C. Warren, and Leslie A. Lyons. "Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon in CLN6." G3: Genes|Genomes|Genetics 10, no. 8 (June 9, 2020): 2741–51. http://dx.doi.org/10.1534/g3.120.401407.

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A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G > A; XM_003987007.5:c.668G > A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat’s clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat’s disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.

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Gao, Luying, Juanjuan Wang, Yuxin Jiang, Qiong Gao, Ying Wang, Xuehua Xi, and Bo Zhang. "The Number of Central Lymph Nodes on Preoperative Ultrasound Predicts Central Neck Lymph Node Metastasis in Papillary Thyroid Carcinoma: A Prospective Cohort Study." International Journal of Endocrinology 2020 (April 14, 2020): 1–6. http://dx.doi.org/10.1155/2020/2698659.

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To evaluate the effectiveness of the number of central compartment lymph nodes (CLNs) on ultrasound (US) in predicting CLN metastasis (CLNM). We prospectively studied 309 papillary thyroid cancer (PTC) patients who underwent thyroidectomy with CLN dissection at our center from May 2017 to July 2017. The number and features of CLNs were evaluated preoperatively via US. All US examinations were performed using a Philips iU 22 or a GE Logiq 9 machine. Correlations between CLNs observed via preoperative US and amount of CLNM were evaluated. We found that ≥2 CLNs on the preoperative US was associated with CLNM (P<0.01). For this feature, the sensitivity, specificity, and area under the curve (AUC) were 54.3%, 66.1%, and 0.61, respectively. The presence of both suspected metastasis and ≥2 CLNs on US had a specificity of 86.5%. In addition, ≥3 CLNs on preoperative US was associated with large-volume CLNM (>5 metastatic CLNs) (P<0.01). For this feature, the sensitivity, specificity and AUC were 54.8%, 74.5% and 0.65, respectively. The presence of both suspected metastasis and ≥3 CLNs on US had a specificity of 84.9%. The presence of suspected metastasis and/or ≥3 CLNs had a sensitivity of 80.6%. Our results suggest that ≥2 and ≥ 3 CLNs on preoperative US may serve as ancillary preoperative markers for predicting CLNM.

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Houweling, P. J., J. A. L. Cavanagh, and I. Tammen. "Radiation hybrid mapping of three candidate genes for bovine neuronal ceroid lipofuscinosis: CLN3, CLN5 and CLN6." Cytogenetic and Genome Research 115, no. 1 (2006): 5–6. http://dx.doi.org/10.1159/000094793.

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Vallen, Elizabeth A., and Frederick R. Cross. "Interaction Between the MEC1-Dependent DNA Synthesis Checkpoint and G1 Cyclin Function in Saccharomyces cerevisiae." Genetics 151, no. 2 (February 1, 1999): 459–71. http://dx.doi.org/10.1093/genetics/151.2.459.

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Abstract The completion of DNA synthesis in yeast is monitored by a checkpoint that requires MEC1 and RAD53. Here we show that deletion of the Saccharomyces cerevisiae G1 cyclins CLN1 and CLN2 suppressed the essential requirement for MEC1 function. Wild-type levels of CLN1 and CLN2, or overexpression of CLN1, CLN2, or CLB5, but not CLN3, killed mec1 strains. We identified RNR1, which encodes a subunit of ribonucleotide reductase, as a high-copy suppressor of the lethality of mec1 GAL1-CLN1. Northern analysis demonstrated that RNR1 expression is reduced by CLN1 or CLN2 overexpression. Because limiting RNR1 expression would be expected to decrease dNTP pools, CLN1 and CLN2 may cause lethality in mec1 strains by causing initiation of DNA replication with inadequate dNTPs. In contrast to mec1 mutants, MEC1 strains with low dNTPs would be able to delay S phase and thereby remain viable. We propose that the essential function for MEC1 may be the same as its checkpoint function during hydroxyurea treatment, namely, to slow S phase when nucleotides are limiting. In a cln1 cln2 background, a prolonged period of expression of genes turned on at the G1-S border, such as RNR1, has been observed. Thus deletion of CLN1 and CLN2 could function similarly to overexpression of RNR1 in suppressing mec1 lethality.

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Loeb, Jonathan D. J., Tatiana A. Kerentseva, Ting Pan, Marisa Sepulveda-Becerra, and Haoping Liu. "Saccharomyces cerevisiae G1 Cyclins Are Differentially Involved in Invasive and Pseudohyphal Growth Independent of the Filamentation Mitogen-Activated Protein Kinase Pathway." Genetics 153, no. 4 (December 1, 1999): 1535–46. http://dx.doi.org/10.1093/genetics/153.4.1535.

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Abstract Several lines of evidence suggest that the morphogenetic transition from the yeast form to pseudohyphae in Saccharomyces cerevisiae may be regulated by the cyclin-dependent kinase (Cdk). To examine this hypothesis, we mutated all of the G1 cyclin genes in strains competent to form pseudohyphae. Interestingly, mutation of each G1 cyclin results in a different filamentation phenotype, varying from a significant defect in cln1/cln1 strains to enhancement of filament production in cln3/cln3 strains. cln1 cln2 double mutants are more defective in pseudohyphal development and haploid invasive growth than cln1 strains. FLO11 transcription, which correlates with the level of invasive growth, is low in cln1 cln2 mutants and high in grr1 cells (defective in proteolysis of Cln1,2), suggesting that Cln1,2/Cdks regulate the pseudohyphal transcriptional program. Epistasis analysis reveals that Cln1,2/Cdk and the filamentation MAP kinase pathway function in parallel in regulating filamentous and invasive growth. Cln1 and Cln2, but not Ste20 or Ste12, are responsible for most of the elevated FLO11 transcription in grr1 strains. Furthermore, phenotypic comparison of various filamentation mutants illustrates that cell elongation and invasion/cell-cell adhesion during filamentation are separable processes controlled by the pseudohyphal transcriptional program. Potential targets for G1 cyclin/Cdks during filamentous growth are discussed.

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Oresic, Kristina, Britta Mueller, and Domenico Tortorella. "Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner." Bioscience Reports 29, no. 3 (April 9, 2009): 173–81. http://dx.doi.org/10.1042/bsr20080143.

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NCLs (neuronal ceroid lipofuscinoses), a group of inherited neurodegenerative lysosomal storage diseases that predominantly affect children, are the result of autosomal recessive mutations within one of the nine cln genes. The wild-type cln gene products are composed of membrane and soluble proteins that localize to the lysosome or the ER (endoplasmic reticulum). However, the destiny of the Cln variants has not been fully characterized. To explore a possible link between ER quality control and processing of Cln mutants, we investigated the fate of two NCL-related Cln6 mutants found in patient samples (Cln6G123D and Cln6M241T) in neuronal-derived human cells. The point mutations are predicted to be in the putative transmembrane domains and most probably generate misfolded membrane proteins that are subjected to ER quality control. Consistent with this paradigm, both mutants underwent rapid proteasome-mediated degradation and complexed with components of the ER extraction apparatus, Derlin-1 and p97. In addition, knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6G123D and Cln6M241T polypeptides. The results implicate ER quality control in the instability of the Cln variants that probably contributes to the development of NCL.

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Cherkasova, Vera, David M. Lyons, and Elaine A. Elion. "Fus3p and Kss1p Control G1 Arrest in Saccharomyces cerevisiae Through a Balance of Distinct Arrest and Proliferative Functions That Operate in Parallel With Far1p." Genetics 151, no. 3 (March 1, 1999): 989–1004. http://dx.doi.org/10.1093/genetics/151.3.989.

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AbstractIn Saccharomyces cerevisiae, mating pheromones activate two MAP kinases (MAPKs), Fus3p and Kss1p, to induce G1 arrest prior to mating. Fus3p is known to promote G1 arrest by activating Far1p, which inhibits three Clnp/Cdc28p kinases. To analyze the contribution of Fus3p and Kss1p to G1 arrest that is independent of Far1p, we constructed far1 CLN strains that undergo G1 arrest from increased activation of the mating MAP kinase pathway. We find that Fus3p and Kss1p both control G1 arrest through multiple functions that operate in parallel with Far1p. Fus3p and Kss1p together promote G1 arrest by repressing transcription of G1/S cyclin genes (CLN1, CLN2, CLB5) by a mechanism that blocks their activation by Cln3p/Cdc28p kinase. In addition, Fus3p and Kss1p counteract G1 arrest through overlapping and distinct functions. Fus3p and Kss1p together increase the expression of CLN3 and PCL2 genes that promote budding, and Kss1p inhibits the MAP kinase cascade. Strikingly, Fus3p promotes proliferation by a novel function that is not linked to reduced Ste12p activity or increased levels of Cln2p/Cdc28p kinase. Genetic analysis suggests that Fus3p promotes proliferation through activation of Mcm1p transcription factor that upregulates numerous genes in G1 phase. Thus, Fus3p and Kss1p control G1 arrest through a balance of arrest functions that inhibit the Cdc28p machinery and proliferative functions that bypass this inhibition.

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L.G, Khachatryan. "Clinical - genetic characteristics of neuronal ceroid lipofuscinosis type 2." Neuroscience and Neurological Surgery 6, no. 4 (September 7, 2020): 01–08. http://dx.doi.org/10.31579/2578-8868/129.

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The article is devoted to the issues of diagnosis and therapy of one of the most severe degenerative diseases in children - neuronal ceroid lipofuscinosis (NCL). This is a group of inherited neurodegenerative diseases related to lysosomal storage diseases characterized by regression of psychomotor development, resistant epileptic seizures, vision failure up to amaurosis. The morphological basis of NCL types is the accumulation of autofluorescence material in tissues (particularly in the brain), similar in structure to ceroids and lipofuscin, which are related to the “aging” and “wear-and-tear” pigments. To date, we know 14 variants of diseases associated with mutations in 13 genes (PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, KPUR, DNAJC5, CTSF, ATP13A2, CTD7).The most common and deeply studied types of NCL are types 1,2,3. According to scientific data, neuronal ceroid lipofuscinosis is the most common neurodegenerative disease associated with epilepsy and an early fatal outcome. The article demonstrates a unique family case with this disease, reports a discussion of issues related to preclinical diagnosis through genetic verification and suggests a necessity for etiopathogenetic therapy. Here we present two children, from one family, a brother and sister. At the time of diagnosis the sister already had a complete clinical picture of the disease and was genetically verified as having NCL type 2. This fact enabled to identify the same disease in her younger brother at preclinical level and to begin his pathogenetic therapy in time. Currently, the treatment of these patients is conducted with the expensive preparation of Cerliponase - alpha (brineura), which is a purified human enzyme obtained through recombinant DNA technology. Brineura is a recombinant human tripeptidyl peptidase-1 (rhTPP1), the main function of which is the cleavage of the N-terminal tripeptides of a wide range of protein substrates. With the example of this family, the dynamics of clinical manifestations in a child with NCL has been demonstrated in detail, and the algorithm of the medical action aimed at leveling off the serious neurological deficit has been shown.

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Barry, Lucy Anne, Graham William Kay, Nadia Lesley Mitchell, Samantha Jane Murray, Nigel P. Jay, and David Norris Palmer. "Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)." PLOS ONE 17, no. 4 (April 11, 2022): e0261544. http://dx.doi.org/10.1371/journal.pone.0261544.

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The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles. Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras. This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.

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Tyers, M., and B. Futcher. "Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes." Molecular and Cellular Biology 13, no. 9 (September 1993): 5659–69. http://dx.doi.org/10.1128/mcb.13.9.5659-5669.1993.

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In the yeast Saccharomyces cerevisiae, the Cdc28 protein kinase controls commitment to cell division at Start, but no biologically relevant G1-phase substrates have been identified. We have studied the kinase complexes formed between Cdc28 and each of the G1 cyclins Cln1, Cln2, and Cln3. Each complex has a specific array of coprecipitated in vitro substrates. We identify one of these as Far1, a protein required for pheromone-induced arrest at Start. Treatment with alpha-factor induces a preferential association and/or phosphorylation of Far1 by the Cln1, Cln2, and Cln3 kinase complexes. This induced interaction depends upon the Fus3 protein kinase, a mitogen-activated protein kinase homolog that functions near the bottom of the alpha-factor signal transduction pathway. Thus, we trace a path through which a mitogen-activated protein kinase regulates a Cdc2 kinase.

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Tyers, M., and B. Futcher. "Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes." Molecular and Cellular Biology 13, no. 9 (September 1993): 5659–69. http://dx.doi.org/10.1128/mcb.13.9.5659.

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In the yeast Saccharomyces cerevisiae, the Cdc28 protein kinase controls commitment to cell division at Start, but no biologically relevant G1-phase substrates have been identified. We have studied the kinase complexes formed between Cdc28 and each of the G1 cyclins Cln1, Cln2, and Cln3. Each complex has a specific array of coprecipitated in vitro substrates. We identify one of these as Far1, a protein required for pheromone-induced arrest at Start. Treatment with alpha-factor induces a preferential association and/or phosphorylation of Far1 by the Cln1, Cln2, and Cln3 kinase complexes. This induced interaction depends upon the Fus3 protein kinase, a mitogen-activated protein kinase homolog that functions near the bottom of the alpha-factor signal transduction pathway. Thus, we trace a path through which a mitogen-activated protein kinase regulates a Cdc2 kinase.

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Leza, Maria A., and Elaine A. Elion. "POG1, a Novel Yeast Gene, Promotes Recovery From Pheromone Arrest via the G1 Cyclin CLN2." Genetics 151, no. 2 (February 1, 1999): 531–43. http://dx.doi.org/10.1093/genetics/151.2.531.

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Abstract In the absence of a successful mating, pheromone-arrested Saccharomyces cerevisiae cells reenter the mitotic cycle through a recovery process that involves downregulation of the mating mitogen-activated protein kinase (MAPK) cascade. We have isolated a novel gene, POG1, whose promotion of recovery parallels that of the MAPK phosphatase Msg5. POG1 confers α-factor resistance when overexpressed and enhances α-factor sensitivity when deleted in the background of an msg5 mutant. Overexpression of POG1 inhibits α-factor-induced G1 arrest and transcriptional repression of the CLN1 and CLN2 genes. The block in transcriptional repression occurs at SCB/MCB promoter elements by a mechanism that requires Bck1 but not Cln3. Genetic tests strongly argue that POG1 promotes recovery through upregulation of the CLN2 gene and that the resulting Cln2 protein promotes recovery primarily through an effect on Ste20, an activator of the mating MAPK cascade. A pog1 cln3 double mutant displays synthetic mutant phenotypes shared by cell-wall integrity and actin cytoskeleton mutants, with no synthetic defect in the expression of CLN1 or CLN2. These and other results suggest that POG1 may regulate additional genes during vegetative growth and recovery.

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Wijnen, Herman, and Bruce Futcher. "Genetic Analysis of the Shared Role of CLN3 and BCK2 at the G1-S Transition in Saccharomyces cerevisiae." Genetics 153, no. 3 (November 1, 1999): 1131–43. http://dx.doi.org/10.1093/genetics/153.3.1131.

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Abstract The transcription complexes SBF and MBF mediate the G1-S transition in the cell cycle of Saccharomyces cerevisiae. In late G1, SBF and MBF induce a burst of transcription in a number of genes, including G1- and S-phase cyclins. Activation of SBF and MBF depends on the G1 cyclin Cln3 and a largely uncharacterized protein called Bck2. We show here that the induction of SBF/MBF target genes by Bck2 depends partly, but not wholly, on SBF and MBF. Unlike Cln3, Bck2 is capable of inducing its transcriptional targets in the absence of functional Cdc28. Our results revealed promoter-specific mechanisms of regulation by Cln3, Bck2, SBF, and MBF. We isolated high-copy suppressors of the cln3 bck2 growth defect; all of these had the ability to increase CLN2 expression. One of these suppressors was the negative regulator of meiosis RME1. Rme1 induces CLN2, and we show that it has a haploid-specific role in regulating cell size and pheromone sensitivity. Genetic analysis of the cln3 bck2 defect showed that CLN1, CLN2, and other SBF/MBF target genes have an essential role in addition to the degradation of Sic1.

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Pierson, Tyler Mark. "Modeling CLN6 with patient-derived IPS cells." Molecular Genetics and Metabolism 120, no. 1-2 (January 2017): S107. http://dx.doi.org/10.1016/j.ymgme.2016.11.272.

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Pierson, Tyler Mark, Maria Gabriella Otero, David Fabian Nonis, and Jaemin Kim. "Modeling CLN6 with IPSC-derived neural cells." Molecular Genetics and Metabolism 126, no. 2 (February 2019): S118. http://dx.doi.org/10.1016/j.ymgme.2018.12.299.

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SHIRO, Yuki, Arisa YAMASHITA, Kana WATANABE, and Tetsuo YAMAZAKI. "CLN6’s luminal tail-mediated functional interference between CLN6 mutants as a novel pathomechanism for the neuronal ceroid lipofuscinoses." Biomedical Research 42, no. 4 (August 12, 2021): 129–38. http://dx.doi.org/10.2220/biomedres.42.129.

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31

Cross, F. R., M. Hoek, J. D. McKinney, and A. H. Tinkelenberg. "Role of Swi4 in cell cycle regulation of CLN2 expression." Molecular and Cellular Biology 14, no. 7 (July 1994): 4779–87. http://dx.doi.org/10.1128/mcb.14.7.4779-4787.1994.

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Expression of the Saccharomyces cerevisiae CLN1 and CLN2 genes is cell cycle regulated, and the genes may be controlled by positive feedback. It has been proposed that positive feedback operates via Cln/Cdc28 activation of the Swi4/Swi6 transcription factor, leading to CLN1 and CLN2 transcription due to Swi4 binding to specific sites (SCBs) in the CLN1 and CLN2 promoters. To test this proposal, we have examined the effects of deletion either of the potential SCBs in the CLN2 promoter or of the SWI4 gene on CLN2 transcriptional control. Deletion of a restriction fragment containing the identified SCBs from the promoter does not prevent cell cycle regulation of CLN2 expression, although expression is lowered at all cell cycle positions. A promoter containing a 5.5-kb plasmid insertion or an independent 2.5-kb insertion at the point of deletion of the SCB-containing restriction fragment also exhibits cell cycle regulation, so involvement of unidentified upstream SCBs is unlikely. Neither Swi4 nor the related Mbp1 transcription factor is required for cell cycle regulation of the intact CLN2 promoter. In contrast, Swi4 (but not Mbp1) is required for correct cell cycle regulation of the insertion/deletion promoter lacking SCB sites. We have extended previous genetic evidence for involvement of Swi4 in some aspect of CLN2 function: a mutant hunt for CLN2 positive regulatory factors yielded only swi4 mutations at saturation. Swi4 may bind to nonconsensus sequences in the CLN2 promoter (possibly in addition to consensus sites), or it may act indirectly to regulate CLN2 expression.

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Cross, F. R., M. Hoek, J. D. McKinney, and A. H. Tinkelenberg. "Role of Swi4 in cell cycle regulation of CLN2 expression." Molecular and Cellular Biology 14, no. 7 (July 1994): 4779–87. http://dx.doi.org/10.1128/mcb.14.7.4779.

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Expression of the Saccharomyces cerevisiae CLN1 and CLN2 genes is cell cycle regulated, and the genes may be controlled by positive feedback. It has been proposed that positive feedback operates via Cln/Cdc28 activation of the Swi4/Swi6 transcription factor, leading to CLN1 and CLN2 transcription due to Swi4 binding to specific sites (SCBs) in the CLN1 and CLN2 promoters. To test this proposal, we have examined the effects of deletion either of the potential SCBs in the CLN2 promoter or of the SWI4 gene on CLN2 transcriptional control. Deletion of a restriction fragment containing the identified SCBs from the promoter does not prevent cell cycle regulation of CLN2 expression, although expression is lowered at all cell cycle positions. A promoter containing a 5.5-kb plasmid insertion or an independent 2.5-kb insertion at the point of deletion of the SCB-containing restriction fragment also exhibits cell cycle regulation, so involvement of unidentified upstream SCBs is unlikely. Neither Swi4 nor the related Mbp1 transcription factor is required for cell cycle regulation of the intact CLN2 promoter. In contrast, Swi4 (but not Mbp1) is required for correct cell cycle regulation of the insertion/deletion promoter lacking SCB sites. We have extended previous genetic evidence for involvement of Swi4 in some aspect of CLN2 function: a mutant hunt for CLN2 positive regulatory factors yielded only swi4 mutations at saturation. Swi4 may bind to nonconsensus sequences in the CLN2 promoter (possibly in addition to consensus sites), or it may act indirectly to regulate CLN2 expression.

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Pierson, Tyler Mark, Yogesh K. Kushwaha, Maria Gabriela Otero, Phillip J. Kenny, Fabian David Nonis, and Jaemin Kim. "Human induced pluripotent stem cell models for CLN6." Molecular Genetics and Metabolism 132, no. 2 (February 2021): S86—S87. http://dx.doi.org/10.1016/j.ymgme.2020.12.206.

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Pierson, Tyler M., Yogesh K. Kushwaha, Hiral Oza, and Maria G. Otero. "Modeling CLN6 with IPSC-derived neurons and glia." Molecular Genetics and Metabolism 138, no. 2 (February 2023): 107269. http://dx.doi.org/10.1016/j.ymgme.2022.107269.

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Di Como, C. J., R. Bose, and K. T. Arndt. "Overexpression of SIS2, which contains an extremely acidic region, increases the expression of SWI4, CLN1 and CLN2 in sit4 mutants." Genetics 139, no. 1 (January 1, 1995): 95–107. http://dx.doi.org/10.1093/genetics/139.1.95.

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Abstract The Saccharomyces cerevisiae SIS2 gene was identified by its ability, when present on a high copy number plasmid, to increase dramatically the growth rate of sit4 mutants. SIT4 encodes a type 2A-related protein phosphatase that is required in late G1 for normal G1 cyclin expression and for bud initiation. Overexpression of SIS2, which contains an extremely acidic carboxyl terminal region, stimulated the rate of CLN1, CLN2, SWI4 and CLB5 expression in sit4 mutants. Also, overexpression of SIS2 in a CLN1 cln2 cln3 strain stimulated the growth rate and the rate of CLN1 and CLB5 RNA accumulation during late G1. The SIS2 protein fractionated with nuclei and was released from the nuclear fraction by treatment with either DNase I or micrococcal nuclease, but not by RNase A. This result, combined with the finding that overexpression of SIS2 is extremely to a strain containing lower than normal levels of histones H2A and H2B, suggests that SIS2 might function to stimulate transcription via an interaction with chromatin.

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Rowley, A., G. C. Johnston, B. Butler, M. Werner-Washburne, and R. A. Singer. "Heat shock-mediated cell cycle blockage and G1 cyclin expression in the yeast Saccharomyces cerevisiae." Molecular and Cellular Biology 13, no. 2 (February 1993): 1034–41. http://dx.doi.org/10.1128/mcb.13.2.1034-1041.1993.

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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.

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Rowley, A., G. C. Johnston, B. Butler, M. Werner-Washburne, and R. A. Singer. "Heat shock-mediated cell cycle blockage and G1 cyclin expression in the yeast Saccharomyces cerevisiae." Molecular and Cellular Biology 13, no. 2 (February 1993): 1034–41. http://dx.doi.org/10.1128/mcb.13.2.1034.

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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.

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kleine Holthaus, Sophia-Martha, Joana Ribeiro, Laura Abelleira-Hervas, Rachael A. Pearson, Yanai Duran, Anastasios Georgiadis, Robert D. Sampson, et al. "Prevention of Photoreceptor Cell Loss in a Cln6 Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells." Molecular Therapy 26, no. 5 (May 2018): 1343–53. http://dx.doi.org/10.1016/j.ymthe.2018.02.027.

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Valdivieso, M. H., K. Sugimoto, K. Y. Jahng, P. M. Fernandes, and C. Wittenberg. "FAR1 is required for posttranscriptional regulation of CLN2 gene expression in response to mating pheromone." Molecular and Cellular Biology 13, no. 2 (February 1993): 1013–22. http://dx.doi.org/10.1128/mcb.13.2.1013-1022.1993.

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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.

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Valdivieso, M. H., K. Sugimoto, K. Y. Jahng, P. M. Fernandes, and C. Wittenberg. "FAR1 is required for posttranscriptional regulation of CLN2 gene expression in response to mating pheromone." Molecular and Cellular Biology 13, no. 2 (February 1993): 1013–22. http://dx.doi.org/10.1128/mcb.13.2.1013.

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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.

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이현경, 우영종, 김명규, 윤보애, and 김영옥. "CLN6 Mutation in a Patient with Progressive Myoclonus Epilepsy." Journal of the korean child neurology society 26, no. 2 (June 2018): 123–27. http://dx.doi.org/10.26815/jkcns.2018.26.2.123.

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Broom, Murray F., and Chaoming Zhou. "Fine mapping of ovine ceroid lipofuscinosisconfirms orthology with CLN6." European Journal of Paediatric Neurology 5 (January 2001): 33–35. http://dx.doi.org/10.1053/ejpn.2000.0431.

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Chapa y Lazo, Bernardo, Steven Bates, and Peter Sudbery. "The G1 Cyclin Cln3 Regulates Morphogenesis in Candida albicans." Eukaryotic Cell 4, no. 1 (January 2005): 90–94. http://dx.doi.org/10.1128/ec.4.1.90-94.2005.

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ABSTRACT In Saccharomyces cerevisiae, the G1 cyclin Cln3 initiates the Start of a mitotic cell cycle in response to size and nutrient inputs. Loss of Cln3 delays but does not prevent Start, due to the eventual Cln3-independent transcription of CLN1 and CLN2. When unbudded cells of the human pathogen Candida albicans were depleted of the G1 cyclin Cln3 they increased in size but did not bud. Thus, unlike S. cerevisiae, Cln3 is essential for budding in C. albicans. However, eventually the large unbudded cells spontaneously produced filamentous forms. The morphology was growth medium dependent; on nutritionally poor medium the polarized outgrowths fulfilled the formal criteria for true hyphae. This state is stable, and continued growth leads to a hyphal mycelium, which invades the agar substratum. Interestingly, it is also required for normal hyphal development, as Cln3-depleted cells develop morphological abnormalities if challenged with hyphal inducing signals such as serum or neutral pH. Taken together, these results show that, in C. albicans, Cln3 has assumed a critical role in coordinating mitotic cell division with differentiation.

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MacKay, Vivian L., Bernard Mai, Laurie Waters, and Linda L. Breeden. "Early Cell Cycle Box-Mediated Transcription ofCLN3 and SWI4 Contributes to the Proper Timing of the G1-to-S Transition in Budding Yeast." Molecular and Cellular Biology 21, no. 13 (July 1, 2001): 4140–48. http://dx.doi.org/10.1128/mcb.21.13.4140-4148.2001.

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ABSTRACT The Cln3-Cdc28 kinase is required to activate the Swi4-Swi6 transcription complex which induces CLN1 andCLN2 transcription in late G1 and drives the transition to S. Cln3 and Swi4 are both rate limiting for G1 progression, and they are coordinately transcribed to peak at the M/G1 boundary. Early cell cycle box (ECB) elements, which confer M/G1-specific transcription, have been found in both promoters, and elimination of all ECB elements from the CLN3 promoter causes both a loss of periodicity and Cln3-deficient phenotypes, which include an extended G1interval and increased cell volume. Mutants lacking the ECB elements in both the CLN3 and SWI4 promoters have low and deregulated levels of CLN transcripts, and the G1-to-S transition for these mutants is delayed and highly variable. These observations support the view that the coordinated rise of Cln3 and Swi4 levels mediated by ECB-dependent transcription controls the timing of the G1-to-S phase transition.

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Best, Hannah L., Nicole J. Neverman, Hollie E. Wicky, Nadia L. Mitchell, Beulah Leitch, and Stephanie M. Hughes. "Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics." Neurobiology of Disease 100 (April 2017): 62–74. http://dx.doi.org/10.1016/j.nbd.2017.01.001.

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Shiro, Yuki, and Tetsuo Yamazaki. "Novel insight into the compound heterozygosity-driven CLN6 disease pathomechanism." Molecular Genetics and Metabolism 135, no. 2 (February 2022): S112. http://dx.doi.org/10.1016/j.ymgme.2021.11.297.

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de los Reyes, Emily, Kathrin Meyer, Lenora Lehwald, Charles Albright, Jeff Castelli, Hai Jiang, Allen Reha, and Jay Barth. "Single-dose AAV9-CLN6 gene transfer stabilizes motor and language function in CLN6-type Batten disease: Interim results from the first clinical gene therapy trial." Molecular Genetics and Metabolism 129, no. 2 (February 2020): S46—S47. http://dx.doi.org/10.1016/j.ymgme.2019.11.101.

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Ho, Yuen, Michael Costanzo, Lynda Moore, Ryuji Kobayashi, and Brenda J. Andrews. "Regulation of Transcription at theSaccharomyces cerevisiae Start Transition by Stb1, a Swi6-Binding Protein." Molecular and Cellular Biology 19, no. 8 (August 1, 1999): 5267–78. http://dx.doi.org/10.1128/mcb.19.8.5267.

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ABSTRACT In Saccharomyces cerevisiae, gene expression in the late G1 phase is activated by two transcription factors, SBF and MBF. SBF contains the Swi4 and Swi6 proteins and activates the transcription of G1 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 G1 phase. In vivo accumulation of Stb1 phosphoforms was dependent on CLN1, CLN2, andCLN3, which encode G1-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 G1 progression and the onset of Start transcription in a cln3Δ strain. Our results suggest a role for STB1 in controlling the timing of Start transcription that is revealed in the absence of the G1regulator CLN3, and they implicate Stb1 as an in vivo target of G1-specific cyclin-dependent kinases.

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Lew, D. J., and S. I. Reed. "Morphogenesis in the yeast cell cycle: regulation by Cdc28 and cyclins." Journal of Cell Biology 120, no. 6 (March 15, 1993): 1305–20. http://dx.doi.org/10.1083/jcb.120.6.1305.

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Abstract:

Analysis of cell cycle regulation in the budding yeast Saccharomyces cerevisiae has shown that a central regulatory protein kinase, Cdc28, undergoes changes in activity through the cell cycle by associating with distinct groups of cyclins that accumulate at different times. The various cyclin/Cdc28 complexes control different aspects of cell cycle progression, including the commitment step known as START and mitosis. We found that altering the activity of Cdc28 had profound effects on morphogenesis during the yeast cell cycle. Our results suggest that activation of Cdc28 by G1 cyclins (Cln1, Cln2, or Cln3) in unbudded G1 cells triggers polarization of the cortical actin cytoskeleton to a specialized pre-bud site at one end of the cell, while activation of Cdc28 by mitotic cyclins (Clb1 or Clb2) in budded G2 cells causes depolarization of the cortical actin cytoskeleton and secretory apparatus. Inactivation of Cdc28 following cyclin destruction in mitosis triggers redistribution of cortical actin structures to the neck region for cytokinesis. In the case of pre-bud site assembly following START, we found that the actin rearrangement could be triggered by Cln/Cdc28 activation in the absence of de novo protein synthesis, suggesting that the kinase may directly phosphorylate substrates (such as actin-binding proteins) that regulate actin distribution in cells.

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Al-Muhaizea, Mohammad A., Zuhair N. Al-Hassnan, and Aziza Chedrawi. "Variant Late Infantile Neuronal Ceroid Lipofuscinosis (CLN6 Gene) in Saudi Arabia." Pediatric Neurology 41, no. 1 (July 2009): 74–76. http://dx.doi.org/10.1016/j.pediatrneurol.2009.01.012.

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Journal articles on the topic 'CLN6'

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