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Identification of evolutionarily conserved genetic regulators of cellular aging.

ABSTRACT: To identify new genetic regulators of cellular aging and senescence, we performed genome-wide comparative RNA profiling with selected human cellular model systems, reflecting replicative senescence, stress-induced premature senescence, and distinct other forms of cellular aging. Gene expression profiles were measured, analyzed, and entered into a newly generated database referred to as the GiSAO database. Bioinformatic analysis revealed a set of new candidate genes, conserved across the majority of the cellular aging models, which were so far not associated with cellular aging, and highlighted several new pathways that potentially play a role in cellular aging. Several candidate genes obtained through this analysis have been confirmed by functional experiments, thereby validating the experimental approach. The effect of genetic deletion on chronological lifespan in yeast was assessed for 93 genes where (i) functional homologues were found in the yeast genome and (ii) the deletion strain was viable. We identified several genes whose deletion led to significant changes of chronological lifespan in yeast, featuring both lifespan shortening and lifespan extension. In conclusion, an unbiased screen across species uncovered several so far unrecognized molecular pathways for cellular aging that are conserved in evolution.

SUBMITTER: Laschober GT

PROVIDER: S-EPMC2997327 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Identification of evolutionarily conserved genetic regulators of cellular aging.

Laschober Gerhard T GT Ruli Doris D Hofer Edith E Muck Christoph C Carmona-Gutierrez Didac D Ring Julia J Hutter Eveline E Ruckenstuhl Christoph C Micutkova Lucia L Brunauer Regina R Jamnig Angelika A Trimmel Daniela D Herndler-Brandstetter Dietmar D Brunner Stefan S Zenzmaier Christoph C Sampson Natalie N Breitenbach Michael M Fröhlich Kai-Uwe KU Grubeck-Loebenstein Beatrix B Berger Peter P Wieser Matthias M Grillari-Voglauer Regina R Thallinger Gerhard G GG Grillari Johannes J Grillari Johannes J Trajanoski Zlatko Z Madeo Frank F Lepperdinger Günter G Jansen-Dürr Pidder P

Aging cell 20101028 6

To identify new genetic regulators of cellular aging and senescence, we performed genome-wide comparative RNA profiling with selected human cellular model systems, reflecting replicative senescence, stress-induced premature senescence, and distinct other forms of cellular aging. Gene expression profiles were measured, analyzed, and entered into a newly generated database referred to as the GiSAO database. Bioinformatic analysis revealed a set of new candidate genes, conserved across the majority ...[more]

PMID: 20883526

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Project description:BackgroundThe p53 tumor suppressor protein is mainly regulated by alterations in the half-life of the protein, resulting in significant differences in p53 protein levels in cells. The major regulator of this process is Mdm2, which ubiquitinates p53 and targets it for proteasomal degradation. This process can be enhanced or reduced by proteins that associate with p53 or Mdm2 and several proteins have been identified with such an activity. Furthermore, additional ubiquitin ligases for p53 have been identified in recent years. Nevertheless, our understanding of how p53 abundance and Mdm2 activity are regulated remains incomplete. Here we describe a cell culture based overexpression screen to identify evolutionarily conserved regulators of the p53/Mdm2 circuit. The results from this large-scale screening method will contribute to a better understanding of the regulation of these important proteins.MethodsExpression screening was based on co-transfection of H1299 cells with pools of cDNA's from a Medaka library together with p53, Mdm2 and, as internal control, Ror2. After cell lysis, SDS-PAGE/WB analysis was used to detect alterations in these proteins.ResultsMore than one hundred hits that altered the abundance of either p53, Mdm2, or both were identified in the primary screen. Subscreening of the library pools that were identified in the primary screen identified several potential novel regulators of p53 and/or Mdm2. We also tested whether the human orthologues of the Medaka genes regulate p53 and/or Mdm2 abundance. All human orthologues regulated p53 and/or Mdm2 abundance in the same manner as the proteins from Medaka, which underscores the suitability of this screening methodology for the identification of new modifiers of p53 and Mdm2.ConclusionsDespite enormous efforts in the last two decades, many unknown regulators for p53 and Mdm2 abundance are predicted to exist. This cross-species approach to identify evolutionarily conserved regulators demonstrates that our Medaka unigene cDNA library represents a powerful tool to screen for these novel regulators of the p53/Mdm2 pathway.

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Identification of evolutionarily conserved genetic regulators of cellular aging.

Publications

Identification of evolutionarily conserved genetic regulators of cellular aging.

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