Peter Deak | University of Szeged (original) (raw)

Papers by Peter Deak

Ubiquitylation is an intracellular chemical reaction in which the small polypeptide, ubiquitin, i... more Ubiquitylation is an intracellular chemical reaction in which the small polypeptide, ubiquitin, is covalently attached to proteins to serve as a versatile signal with proteolytic and non-proteolytic functions. Although the importance of ubiquitylation was first recognized in the process of proteasome-mediated protein degradation, its regulatory potential has since been extended considerably. It is now known that through an elaborate and diverse set of ubiquitylating and deubiquitylating enzymes, the ubiquitin-proteasome system affects practically all intracellular processes. Not surprisingly, alterations in the ubiquitylating system have been linked to the development of various human diseases, including neurodegenerative disorders and cancer. Here, we highlight the most important components and processes of the UPS, and then demonstrate in a few examples connections between aberrations in ubiquitylation and the pathogenesis of certain diseases. Acta Biol Szeged 59(Suppl.2):261-273 ...

ABSTRACTDeubiquitinating (DUB) enzymes free covalently linked ubiquitins from ubiquitin-ubiquitin... more ABSTRACTDeubiquitinating (DUB) enzymes free covalently linked ubiquitins from ubiquitin-ubiquitin and ubiquitin-protein conjugates, and thereby maintain the equilibrium between free and conjugated ubiquitins and regulate ubiquitin-mediated cellular processes. The present genetic analyses of mutant phenotypes demonstrate that loss of Usp14 function results in male sterility, with defects in spermatid individualization and reduced testicular free monoubiquitin levels. These phenotypes were rescued by germline specific overexpression of wild type Usp14. Synergistic genetic interactions with Ubi-p63E and cycloheximide sensitivity suggest that ubiquitin shortage is a primary cause of male sterility. In addition, Usp14 is predominantly expressed in testes in Drosophila, and differential expression patterns may be causative of testis-specific loss of function Usp14 phenotypes. Collectively, these results suggest a major role of Usp14 in maintaining normal steady state free monoubiquitin le...

Background: Approximately one-third of the Drosophila kinome has been ascribed some cell-cycle fu... more Background: Approximately one-third of the Drosophila kinome has been ascribed some cell-cycle function. However, little is known about which of its 117 protein phosphatases (PPs) or subunits have counteracting roles. Results: We investigated mitotic roles of PPs through systematic RNAi. We found that G 2-M progression requires Puckered, the JNK MAP-kinase inhibitory phosphatase and PP2C in addition to string (Cdc25). Strong mitotic arrest and chromosome congression failure occurred after Pp1-87B downregulation. Chromosome alignment and segregation defects also occurred after knockdown of PP1-Flapwing, not previously thought to have a mitotic role. Reduction of several nonreceptor tyrosine phosphatases produced spindle and chromosome behavior defects, and for corkscrew, premature chromatid separation. RNAi of the dual-specificity phosphatase, Myotubularin, or the related Sbf ''antiphosphatase'' resulted in aberrant mitotic chromosome behavior. Finally, for PP2A, knockdown of the catalytic or A subunits led to bipolar monoastral spindles, knockdown of the Twins B subunit led to bridged and lagging chromosomes, and knockdown of the B 0 Widerborst subunit led to scattering of all mitotic chromosomes. Widerborst was associated with MEI-S332 (Shugoshin) and required for its kinetochore localization. Conclusions: We identify cell-cycle roles for 22 of 117 Drosophila PPs. Involvement of several PPs in G 2 suggests multiple points for its regulation. Major mitotic roles are played by PP1 with tyrosine PPs and Myotubularin-related PPs having significant roles in regulating chromosome behavior. Finally, depending upon its regulatory subunits, PP2A regulates spindle bipolarity, kinetochore function, and progression into anaphase. Discovery of several novel cell-cycle PPs identifies a need for further studies of protein dephosphorylation.

OTKA 60723 pályázat zárójelentés Részletes szakmai beszámoló a pályázat munkaterve alapján Kalpai... more OTKA 60723 pályázat zárójelentés Részletes szakmai beszámoló a pályázat munkaterve alapján Kalpainok foszforilációjának vizsgálata Rekombináns fehérjékkel megvizsgáltuk a patkány m-kalpain, a humán kalpasztatin és a Drosophila kalpain B in vitro foszforilálhatóságát. Igazoltuk a kalpain m foszforilációját

Insect Biochemistry, 1988

The moulting hormone (MH) receptor level has been measured in embryonic first and third larval st... more The moulting hormone (MH) receptor level has been measured in embryonic first and third larval stages of D. mekznogaster. Fluctuating receptor levels were found in all stages investigated with prominent peaks in 16 h embryos, 18 h first instar and 13 and 33 h third instar larvae. The receptor level peaks occur subsequent to MH peaks. Experimental 20-hydroxyecdysone feeding resulted in a rapid increase of the receptor level, which was dependent upon protein synthesis. When the conversion of ecdysone to 20-hydroxyecdysone was effectively inhibited by the drug, methyrapone, ecdysone was not effective in this receptor level augmentation. The receptor selectively binds 20-hydroxyecdysone only among the several ecdysteroids present in the embryo, providing further evidence that 20-hydroxyecdysone is the active hormone. The different efficacy of these steroids parallels the extent of receptor binding, suggesting the involvement of the receptor in its augmentation. The role of the receptor level in mediating the action of MH is discussed.

Developmental Biology, 2000

The Drosophila importin-␣3 gene was isolated through its interaction with the large subunit of th... more The Drosophila importin-␣3 gene was isolated through its interaction with the large subunit of the DNA polymerase ␣ in a two-hybrid screen. The predicted protein sequence of Importin-␣3 is 65-66% identical to those of the human and mouse importin-␣3 and ␣4 and 42.7% identical to that of Importin-␣2 (Oho31/Pendulin), the previously reported Drosophila homologue. Both Importin-␣3 and Importin-␣2 interact with similar subsets of proteins in vitro, one of which is Ketel, the importin-␤ homologue of Drosophila. importin-␣3 is an essential gene, whose encoded protein is expressed throughout development. During early embryogenesis, Importin-␣3 accumulates at the nuclear membrane of cleavage nuclei, whereas after blastoderm formation it is characteristically found within the interphase nuclei. Nuclear localisation is seen in several tissues throughout subsequent development. During oogenesis its concentration within the nurse cell nuclei increases during stages 7-10, concomitant with a decline in levels in the oocyte nucleus. Mutation of importin-␣3 results in lethality throughout pupal development. Surviving females are sterile and show arrest of oogenesis at stages 7-10. Thus, Importin-␣3-mediated nuclear transport is essential for completion of oogenesis and becomes limiting during pupal development. Since they have different expression patterns and subcellular localisation profiles, we suggest that the two importin-␣ homologues are not redundant in the context of normal Drosophila development.

Cell, 1996

domain of the activated receptor. With its SH3 domains, *Theodor Boveri Institut fü r Biowissensc... more domain of the activated receptor. With its SH3 domains, *Theodor Boveri Institut fü r Biowissenschaften DRK interacts with the carboxy-terminal region of the Lehrstuhl fü r Genetik guanine nucleotide exchange factor Son of Sevenless Universitä t Würzburg (SOS) and brings it in close proximity to Ras1. SOS D-97074 Wü rzburg activates Ras1 by catalyzing the GDP-GTP exchange Federal Republic of Germany (reviewed by McCormick, 1993; Pawson, 1995). † Zoologisches Institut The simple linear model of RTK signal transduction Universitä t Zü rich has been questioned by the large bulk of biochemical CH-8057 Zü rich evidence for a variety of proteins that are bound to Switzerland activated RTKs (Kazlauskas,

Development, 2008

The endocycle is a commonly observed variant cell cycle in which cells undergo repeated rounds of... more The endocycle is a commonly observed variant cell cycle in which cells undergo repeated rounds of DNA replication with no intervening mitosis. How the cell cycle machinery is modified to transform a mitotic cycle into endocycle has long been a matter of interest. In both plants and animals, the transition from the mitotic cycle to the endocycle requires Fzr/Cdh1, a positive regulator of the Anaphase-Promoting Complex/Cyclosome (APC/C). However, because many of its targets are transcriptionally downregulated upon entry into the endocycle, it remains unclear whether the APC/C functions beyond the mitotic/endocycle boundary. Here, we report that APC/CFzr/Cdh1 activity is required to promote the G/S oscillation of the Drosophila endocycle. We demonstrate that compromising APC/C activity, after cells have entered the endocycle, inhibits DNA replication and results in the accumulation of multiple APC/C targets, including the mitotic cyclins and Geminin. Notably, our data suggest that the ...

PLOS ONE, 2015

Protein ubiquitylation is a dynamic process that affects the function and stability of proteins a... more Protein ubiquitylation is a dynamic process that affects the function and stability of proteins and controls essential cellular processes ranging from cell proliferation to cell death. This process is regulated through the balanced action of E3 ubiquitin ligases and deubiquitylating enzymes (DUB) which conjugate ubiquitins to, and remove them from target proteins, respectively. Our genetic analysis has revealed that the deubiquitylating enzyme DmUsp5 is required for maintenance of the ubiquitin equilibrium, cell survival and normal development in Drosophila. Loss of the DmUsp5 function leads to late larval lethality accompanied by the induction of apoptosis. Detailed analyses at a cellular level demonstrated that DmUsp5 mutants carry multiple abnormalities, including a drop in the free monoubiquitin level, the excessive accumulation of free polyubiquitins, polyubiquitylated proteins and subunits of the 26S proteasome. A shortage in free ubiquitins results in the induction of a ubiquitin stress response previously described only in the unicellular budding yeast. It is characterized by the induction of the proteasome-associated deubiquitylase DmUsp14 and sensitivity to cycloheximide. Removal of DmUsp5 also activates the pro-apoptotic machinery thereby resulting in widespread apoptosis, indicative of an anti-apoptotic role of DmUsp5. Collectively, the pleiotropic effects of a loss of DmUsp5 function can be explained in terms of the existence of a limited pool of free monoubiquitins which makes the ubiquitindependent processes mutually interdependent.

European Journal of Entomology, 1994

Pathology & Oncology Research, 2016

The Journal of Neuroscience, Feb 1, 1997

The International Journal of Developmental Biology, 2002

A collection of 1609 recessive P-lethal mutations on the third chromosome was tested in germline ... more A collection of 1609 recessive P-lethal mutations on the third chromosome was tested in germline clones for effects on egg differentiation and embryonic development. In 164 lines, normal differentiation of the egg chamber is prevented and in 841 lines, embryos develop abnormally. This latter group of maternal-effect mutations was subdivided into 23 classes based on the cuticular phenotypes. Our collection comprises new alleles of previously characterized genes (e.g. kayak, punt, string, tramtrack). For some of the genes identified in this screen, a maternal contribution to embryonic development has not been described previously (e.g. extramacrochaete, Trithorax-like, single minded, couch potato, canoe). The genes classified in our study with a dual function during oogenesis and embryogenesis not only substantially extends the existing collection of maternal-effect genes but will also aid further understanding of how patterning of the Drosophila embryo is controlled by the maternal genome.

The International journal of developmental biology, 2002

The absent small and homeotic (ash2) gene is a member of the trithorax group of positive transcri... more The absent small and homeotic (ash2) gene is a member of the trithorax group of positive transcriptional regulators of the homeotic genes. In this work we present evidence that loss-of-function of ash2 results in patterning alterations in the developing wing. Homozygous adults of the weak allele ash2(112411) develop extra cross-veins. However, clonal analysis of a stronger allele, ash2(11), shows that this allele results in reduction of intervein tissue and increase of longitudinal veins and cross-vein tissue in the wing except the region between vein L3 and L4. These results suggest that ash2 function is required for both activation of intervein tissue and repression of vein tissue. Moreover, we have found that cross-vein development can be rescued in the absence of crossveinless-2 when the levels of ash2 were reduced.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997

Mutations in the seizure (sei) locus cause temperature-induced hyperactivity, followed by paralys... more Mutations in the seizure (sei) locus cause temperature-induced hyperactivity, followed by paralysis. Gene cloning studies have established that the seizure gene product is the Drosophila homolog of HERG, a member of the eag family of K+ channels implicated in one form of hereditary long QT syndrome in humans. A series of five null alleles with premature stop codons are all recessive, but viable. A missense mutation in the sei gene, which changes the charge at a conserved glutamate residue near the outer mouth of the pore, has a semidominant phenotype, suggesting that the mutant seizure protein acts as a poison in a multimeric complex. Transformation rescue of a null allele with a cDNA under the control of an inducible promoter demonstrates that induced expression of seizure potassium channels in adults rescues the paralytic phenotype. This rescue decays with a t1/2 of approximately 1-1.5 d after gene induction is discontinued, providing the first estimate of ion channel stability in...

Genetics, 1995

Voltage-sensitive sodium channels play a key role in nerve cells where they are responsible for t... more Voltage-sensitive sodium channels play a key role in nerve cells where they are responsible for the increase in sodium permeability during the rising phase of action potentials. In Drosophila melanogaster a subset of temperature-sensitive paralytic mutations affect sodium channel function. One such mutation is temperature-induced paralysis locus E (tipE), which has been shown by electrophysiology and ligand binding studies to reduce sodium channel numbers. Three new gamma-ray-induced tipE alleles associated with either visible deletions in 64AB or a translocation breakpoint within 64B2 provide landmarks for positional cloning of tipE. Beginning with the flanking cloned gene Ras2, a 140-kb walk across the translocation breakpoint was completed. Germline transformation using a 42-kb cosmid clone and successively smaller subclones localized the tipE gene within a 7.4-kb genomic DNA segment. Although this chromosome region is rich in transcripts, only three overlapping mRNAs (5.4, 4.4, ...