| Abstract: |
We report an unexpected role for Tel2 in the expression of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Although Tel2 was identified as a budding yeast gene required for the telomere length maintenance, we found no obvious telomeric function for mammalian Tel2. Targeted gene deletion showed that mouse Tel2 is essential in embryonic development, embryonic stem (ES) cells, and embryonic fibroblasts. Conditional deletion of Tel2 from embryonic fibroblasts compromised their response to IR and UV, diminishing the activation of checkpoint kinases and their downstream effectors. The effects of Tel2 deletion correlated with significantly reduced protein levels for the PI3K-related kinases ataxia telangiectasia mutated (ATM), ATM and Rad3 related (ATR), DNA-dependent protein kinase catalytic subunit ataxia (DNA-PKcs). Tel2 deletion also elicited specific depletion of the mammalian target of rapamycin (mTOR), suppressor with morphological effect on genitalia 1 (SMG1), and transformation/transcription domain-associated protein (TRRAP), and curbed mTOR signaling, indicating that Tel2 affects all six mammalian PIKKs. While Tel2 deletion did not alter PIKK mRNA levels, in vivo pulse labeling experiments showed that Tel2 controls the stability of ATM and mTOR. Each of the PIKK family members associated with Tel2 in vivo and in vitro experiments indicated that Tel2 binds to part of the HEAT repeat segments of ATM and mTOR. These data identify Tel2 as a highly conserved regulator of PIKK stability. © 2007 Elsevier Inc. All rights reserved. |
| Keywords: |
signal transduction; controlled study; protein expression; unclassified drug; human cell; gene deletion; dna-binding proteins; nonhuman; ultraviolet radiation; cell proliferation; proteins; phenotype; telomere; mammalia; animals; cell cycle proteins; mice; dna damage; cells, cultured; protein kinases; signaling; embryonic stem cell; protein; protein binding; down-regulation; genotype; embryo development; hela cells; transfection; mice, inbred c57bl; mice, transgenic; nuclear proteins; gene expression regulation, developmental; enzyme regulation; transcription regulation; protein processing, post-translational; recombinant fusion proteins; rna, messenger; protein-serine-threonine kinases; mammalian target of rapamycin; tumor suppressor proteins; 1-phosphatidylinositol 3-kinase; fibroblast; fibroblasts; atm protein; adaptor proteins, signal transducing; cellbio; embryo, mammalian; yeast; saccharomycetales; protein kinase; fungal gene; ataxia telangiectasia; gene expression regulation, enzymologic; checkpoint kinase rad3; enzyme stability; transformation transcription domain associated protein; dna dependent protein kinase; dna-activated protein kinase; telomere-binding proteins; phosphatidylinositol 3 kinase related protein kinase; suppressor with morphological effect on genitalia 1 protein
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