PMID- 18160036
OWN - NLM
STAT- MEDLINE
DCOM- 20080207
LR  - 20211203
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 131
IP  - 7
DP  - 2007 Dec 28
TI  - Tel2 regulates the stability of PI3K-related protein kinases.
PG  - 1248-59
AB  - 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.
FAU - Takai, Hiroyuki
AU  - Takai H
AD  - Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York 
      Avenue, New York, NY 10065, USA.
FAU - Wang, Richard C
AU  - Wang RC
FAU - Takai, Kaori K
AU  - Takai KK
FAU - Yang, Haijuan
AU  - Yang H
FAU - de Lange, Titia
AU  - de Lange T
LA  - eng
GR  - K08 CA164047/CA/NCI NIH HHS/United States
GR  - CA076027/CA/NCI NIH HHS/United States
GR  - GM07739/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Telomere-Binding Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (transformation-transcription domain-associated protein)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (Atr protein, mouse)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (Atm protein, mouse)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - DNA Damage
MH  - DNA-Activated Protein Kinase/metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - Down-Regulation
MH  - Embryo, Mammalian
MH  - Fibroblasts/enzymology/*metabolism/radiation effects
MH  - Gene Deletion
MH  - Gene Expression Regulation, Developmental
MH  - Gene Expression Regulation, Enzymologic
MH  - Genotype
MH  - HeLa Cells
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Nuclear Proteins/metabolism
MH  - Phenotype
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Protein Binding
MH  - Protein Kinases/*metabolism
MH  - *Protein Processing, Post-Translational
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - RNA, Messenger/metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Telomere-Binding Proteins/genetics/*metabolism
MH  - Transfection
MH  - Tumor Suppressor Proteins/metabolism
EDAT- 2007/12/28 09:00
MHDA- 2008/02/08 09:00
CRDT- 2007/12/28 09:00
PHST- 2007/04/23 00:00 [received]
PHST- 2007/07/27 00:00 [revised]
PHST- 2007/10/30 00:00 [accepted]
PHST- 2007/12/28 09:00 [pubmed]
PHST- 2008/02/08 09:00 [medline]
PHST- 2007/12/28 09:00 [entrez]
AID - S0092-8674(07)01415-8 [pii]
AID - 10.1016/j.cell.2007.10.052 [doi]
PST - ppublish
SO  - Cell. 2007 Dec 28;131(7):1248-59. doi: 10.1016/j.cell.2007.10.052.