La trisomie 4p

Résumé Trois nouveaux cas de trisomie 4p sont rapportés. Deux observés chez des germains sont liés à une translocation maternelle t (4;15). Le troisième cas est dû à une duplication en miroir du bras court du chromosome 4, il s'agit du premier cas de trisomie 4p sans remaniement parental équilibré. Les principales caractéristiques cliniques et chromosomiques du syndrome sont étudiées à partir des observations de la littérature.

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Trisomy 4pThree new observations

Summary Three new observations of trisomy 4p are reported. Two are due to a maternal translocation t(4;15). The third is due to a mirror duplication, it is the first case of trisomy 4p without balanced parental rearrangement. The very characteristic phenotype is compared to that of 13 other patients already reported in the literature.

     

Irs4p and Tax4p: two redundant EH domain proteins involved in autophagy

Proteins carrying EPS15 homology (EH) domains are present from yeast to mammals. The characterized members of this protein family are all involved in intracellular trafficking, typically endocytosis and endocytic recycling. We focused on two members of this family in Saccharomyces cerevisiae Irs4p and Tax4p, whose functions are less well characterized. We show that the deletion of IRS4 altered the function of a neighboring gene, VPS51 , involved in endocytic recycling. The irs4Δtax4Δ cells complemented for the loss of Vps51p ( irs4Δtax4Δ *) display no defects in endocytosis and endosomal recycling, clearly differentiating these two EH proteins from the other protein family members. Because Irs4p is phosphorylated when autophagy is induced, we studied the potential role of these two proteins in this latter process. We observed a loss of viability upon starvation in irs4Δtax4Δ* cells because of a delay in bulk autophagy. Irs4p and Tax4p are also required for pexophagy but not for the cytoplasm-to-vacuole pathway. In growing cells, Irs4p and Tax4p colocalized to few cytoplasmic puncta distinct from endosomes and Golgi compartments. In conditions inducing autophagy, Irs4p and Tax4p partially localized to the pre-autophagosomal structure (PAS) and are required to efficiently recruit to the PAS Atg17p, a factor modulating the autophagic response. We propose that Irs4p and Tax4p are two redundant modulators of the autophagic processes acting upstream from Atg17p, possibly in the signaling events leading to the activation of the autophagic machinery in response to starvation.     

Differential post-transcriptional regulation of two Ink4 proteins,p18Ink4c and p19Ink4d

Cyclin(-D-)-dependent kinase (Cdk) inhibitors of the Ink4 family specifically bind to Cdk4 and Cdk6, but not to other Cdks. Ink4c and Ink4d mRNAs are maximally and periodically expressed during the G2/M phase of the cell division cycle, but the abundance of their encoded proteins is regulated through distinct mechanisms. Both proteins undergo polyubiquitination, but the half life of p18Ink4c (~10 hours) is much longer than that of p19Ink4d (~2.5 hours). Lysines 46 and 112 are preferred sites of ubiquitin conjugation in p18Ink4c, although substitution of these and other lysine residues with arginine, particularly in combination, triggers protein misfolding and accelerates p18Ink4c degradation. When tethered to either catalytically active or inactive Cdk4 or Cdk6, polyubiquitination of p18Ink4c is inhibited, and the protein is further stabilized. Conversely, in competing with p18Ink4c for binding to Cdks, cyclin D1 accelerates p18Ink4c turnover. In direct contrast, polyubiquitination of p19Ink4d is induced by its association with Cdks, whereas cyclin D1 overexpression retards p19Ink4d degradation. Although it has been generally assumed that p18Ink4c and p19Ink4d are biochemically similar Cdk inhibitors, the major differences in their stability and turnover are likely key to understanding their distinct biological functions.     

Trisomy 4p14 leads to 4pter with translocation t(4;15)(p14;p12) in the father.

A trisomy 4p14 leads to 4pter in a 15-year-old girl is reported. The main features are physical and mental retardation and the absence of gross malformations. The relevance of other symptoms found in the patient is discussed.     

Hand dermatoglyphics in trisomy 4p

Summary A dermatoglyphic analysis of the hands of 16 patients with trisomy for the short arm of chromosome 4 has revealed an increased frequency of whorl patterns on fingertips, presence of axial triradii in position t on palms and an increase of the main line index.Although of little diagnostic value these changes must be included in the constellation of major signs which characterize the 4p trisomy syndrome.     

Familial interstitial deletion of chromosome 4 (p15.2p16.1)

Interstitial deletion of the proximal short arm of chromosome 4, extending from p14 to p16.1 region, results in a distinct clinical syndrome. This proximal 4p deletion syndrome is characterized by variable degrees of mental retardation, unusual facies and minor dysmorphic features. Majority of the patients also show a tall, ectomorphic habitus and normal to excessive linear growth with age. While there have been several cases of such interstitial del(4p) cases reported, familial transmission of this condition has not been documented in the literature. This is the first report of a familial transmission of proximal del(4p) from a mother to her daughter, with both patients showing similar features. This report of the familial transmission of del(4p) has wider implications in genetic counseling.     

SOX4能与p53蛋白发生相互作用

目的：研究SOX4和p53蛋白之间的相互作用。方法：应用GSTpull-down、免疫共沉淀实验验证相互作用。结果：GSTpulldown实验证实SOX4能结合GST-p53融合蛋白,但不能结合GST蛋白;免疫共沉淀实验也证明,SOX4与p53能在细胞内发生相互作用。结论：SOX4能与p53发生相互作用,为p53信号通路的研究提供了新的线索。     

Function of the ski4p (Csl4p) and Ski7p proteins in 3'-to-5' degradation of mRNA

One of two general pathways of mRNA decay in the yeast Saccharomyces cerevisiae occurs by deadenylation followed by 3'-to-5' degradation of the mRNA body. Previous results have shown that this degradation requires components of the exosome and the Ski2p, Ski3p, and Ski8p proteins, which were originally identified due to their superkiller phenotype. In this work, we demonstrate that deletion of the SKI7 gene, which encodes a putative GTPase, also causes a defect in 3'-to-5' degradation of mRNA. Deletion of SKI7, like deletion of SKI2, SKI3, or SKI8, does not affect various RNA-processing reactions of the exosome. In addition, we show that a mutation in the SKI4 gene also causes a defect in 3'-to-5' mRNA degradation. We show that the SKI4 gene is identical to the CSL4 gene, which encodes a core component of the exosome. Interestingly, the ski4-1 allele contains a point mutation resulting in a mutation in the putative RNA binding domain of the Csl4p protein. This point mutation strongly affects mRNA degradation without affecting exosome function in rRNA or snRNA processing, 5' externally transcribed spacer (ETS) degradation, or viability. In contrast, the csl4-1 allele of the same gene affects rRNA processing but not 3'-to-5' mRNA degradation. We identify csl4-1 as resulting from a partial-loss-of-function mutation in the promoter of the CSL4 gene. These data indicate that the distinct functions of the exosome can be separated genetically and suggest that the RNA binding domain of Csl4p may have a specific function in mRNA degradation.     

Ccr4p is the catalytic subunit of a Ccr4p/Pop2p/Notp mRNA deadenylase complex in Saccharomyces cerevisiae

The major pathways of mRNA turnover in eukaryotic cells are initiated by shortening of the poly(A) tail. Recent work has identified Ccr4p and Pop2p as components of the major cytoplasmic deadenylase in yeast. We now demonstrate that CCR4 encodes the catalytic subunit of the deadenylase and that Pop2p is dispensable for catalysis. In addition, we demonstrate that at least some of the Ccr4p/Pop2p-associated Not proteins are cytoplasmic, and lesions in some of the NOT genes can lead to defects in mRNA deadenylation rates. The Ccr4p deadenylase is inhibited in vitro by addition of the poly(A) binding protein (Pab1p), suggesting that dissociation of Pab1p from the poly(A) tail may be rate limiting for deadenylation in vivo. In addition, the rapid deadenylation of the COX17 mRNA, which is controlled by a member of the Pumilio family of deadenylation activators Puf3p, requires an active Ccr4p/Pop2p/Not deadenylase. These results define the Ccr4p/Pop2p/Not complex as the cytoplasmic deadenylase in yeast and identify positive and negative regulators of this enzyme complex.     

Interaction of Saccharomyces Cdc13p with Pol1p, Imp4p, Sir4p and Zds2p is involved in telomere replication, telomere maintenance and cell growth control

Telomeres are the physical ends of eukaryotic chromosomes. They are important for maintaining the integrity of chromosomes and this function is mediated through a number of protein factors. In Saccharomyces cerevisiae, Cdc13p binds to telomeres and affects telomere maintenance, telomere position effects and cell cycle progression through G₂/M phase. We identified four genes encoding Pol1p, Sir4p, Zds2p and Imp4p that interact with amino acids 1–252 of Cdc13p using a yeast two-hybrid screening system. Interactions of these four proteins with Cdc13p were through direct protein–protein interactions as judged by in vitro pull-down assays. Direct protein–protein interactions were also observed between Pol1p–Imp4p, Pol1p–Sir4p and Sir4p–Zds2p, whereas no interaction was detected between Imp4p–Sir4p and Zds2p–Imp4p, suggesting that protein interactions were specific in the complex. Pol1p was shown to interact with Cdc13p. Here we show that Zds2p and Imp4p also form a stable complex with Cdc13p in yeast cells, because Zds2p and Imp4p co-immunoprecipitate with Cdc13p, whereas Sir4p does not. The function of the N-terminal 1–252 region of Cdc13p was also analyzed. Expressing Cdc13(252–924)p, which lacks amino acids 1–252 of Cdc13p, causes defects in progressive cell growth and eventually arrested in the G₂/M phase of the cell cycle. These growth defects were not caused by progressive shortening of telomeres because telomeres in these cells were long. Point mutants in the amino acids 1–252 region of Cdc13p that reduced the interaction between Cdc13p and its binding proteins resulted in varying level of defects in cell growth and telomeres. These results indicate that the interactions between Cdc13(1–252)p and its binding proteins are important for the function of Cdc13p in telomere regulation and cell growth. Together, our results provide evidence for the formation of a Cdc13p-mediated telosome complex through its N-terminal region that is involved in telomere maintenance, telomere length regulation and cell growth control.     

Chemical genetic analysis of the budding-yeast p21-activated kinase Cla4p

The p21-activated kinases (PAKs) are effectors for the Rho-family GTPase Cdc42p. Here we define the in vivo function of the kinase activity of the budding yeast PAK Cla4p, using cla4 alleles that are specifically inhibited by a cell-permeable compound that does not inhibit the wild-type kinase. CLA4 kinase inhibition in cells lacking the partially redundant PAK Ste20p causes reversible SWE1-dependent cell-cycle arrest and gives rise to narrow, highly elongated buds in which both actin and septin are tightly polarized to bud tips. Inhibition of Cla4p does not prevent polarization of F-actin, and cytokinesis is blocked only in cells that have not formed a bud before inhibitor treatment; cell polarization and bud emergence are not affected by Cla4p inhibition. Although localization of septin to bud necks is restored in swe1Delta cells, cytokinesis remains defective. Inhibition of Cla4p activity in swe1Delta cells causes a delay of bud emergence after cell polarization, indicating that this checkpoint may mediate an adaptive response that is capable of promoting budding when Cla4p function is reduced. Our data indicate that CLA4 PAK activity is required at an early stage of budding, after actin polarization and coincident with formation of the septin ring, for early bud morphogenesis and assembly of a cytokinesis site.