title: Tel2 regulates the stability of PI3K-related protein kinases.
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.
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takai
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wang
authors.forename: Kaori K
authors.initials: KK
authors.lastname: Takai
authors.forename: Haijuan
authors.initials: H
authors.lastname: Yang
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D058570:TOR Serine-Threonine Kinases; D034501:Telomere-Binding Proteins; D025521:Tumor Suppressor Proteins; C113829:transformation-transcription domain-associated protein; C576897:Atr protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse