PMID- 22493284
OWN - NLM
STAT- MEDLINE
DCOM- 20120815
LR  - 20240318
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 22
DP  - 2012 May 25
TI  - Ataxia-Telangiectasia, Mutated (ATM)/Nuclear Factor kappa light chain enhancer of 
      activated B cells (NFkappaB) signaling controls basal and DNA damage-induced 
      transglutaminase 2 expression.
PG  - 18330-41
LID - 10.1074/jbc.M112.339317 [doi]
AB  - Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that cross-links 
      proteins and its overexpression, linked to a drug resistant phenotype, is 
      commonly observed in cancer cells. Further, up-regulation of TG2 expression 
      occurs during response to various forms of cell stress; however, the molecular 
      mechanisms that drive inducible expression of the TG2 gene (TGM2) require 
      elucidation. Here we show that genotoxic stress induces TG2 expression through 
      the Ataxia-Telangiectasia, Mutated (ATM)/Nuclear Factor kappa light chain enhancer of 
      activated B cells (NFkappaB) signaling pathway. We further document that NFkappaB is both 
      necessary and sufficient to drive constitutive TG2 expression in cultured cell 
      lines. Additionally, shRNA-mediated knockdown or pharmacological inhibition of 
      the ATM kinase results in reduced constitutive TG2 expression and NFkappaB 
      transcriptional activity. We document that the NFkappaB subunit p65 (RelA) interacts 
      with two independent consensus NFkappaB binding sites within the TGM2 promoter, that 
      mutation of either site or pharmacological inhibition of NFkappaB reduces TGM2 
      promoter activity, and genotoxic stress drives heightened association of p65 with 
      the TGM2 promoter. Finally, we observed that knockdown of either p65 or ATM in 
      MDA-MB-468 breast cancer cells expressing recombinant TG2 partially reduces 
      resistance to doxorubicin, indicating that the drug resistance linked to 
      overexpression of TG2 functions, in part, through p65 and ATM. This work 
      establishes a novel ATM-dependent signaling loop where TG2 and NFkappaB activate each 
      other resulting in sustained activation of NFkappaB and acquisition of a 
      drug-resistant phenotype.
FAU - Ai, Lingbao
AU  - Ai L
AD  - Department of Biochemistry and Molecular Biology, University of Florida College 
      of Medicine, Gainesville, Florida 32610, USA.
FAU - Skehan, Ryan R
AU  - Skehan RR
FAU - Saydi, John
AU  - Saydi J
FAU - Lin, Tong
AU  - Lin T
FAU - Brown, Kevin D
AU  - Brown KD
LA  - eng
GR  - R01 CA102289/CA/NCI NIH HHS/United States
GR  - R01-CA102289/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120404
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA Primers)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (TGM2 protein, human)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2)
RN  - EC 2.3.2.13 (Transglutaminases)
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 (Protein Serine-Threonine Kinases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Base Sequence
MH  - Cell Cycle Proteins/*metabolism
MH  - Cell Line, Tumor
MH  - DNA Damage
MH  - DNA Primers
MH  - DNA-Binding Proteins/*metabolism
MH  - GTP-Binding Proteins/*metabolism
MH  - Humans
MH  - NF-kappa B/*metabolism
MH  - Protein Glutamine gamma Glutamyltransferase 2
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - RNA Interference
MH  - Real-Time Polymerase Chain Reaction
MH  - *Signal Transduction
MH  - Transcription, Genetic
MH  - Transglutaminases/*metabolism
MH  - Tumor Suppressor Proteins/*metabolism
PMC - PMC3365769
EDAT- 2012/04/12 06:00
MHDA- 2012/08/16 06:00
PMCR- 2013/05/25
CRDT- 2012/04/12 06:00
PHST- 2012/04/12 06:00 [entrez]
PHST- 2012/04/12 06:00 [pubmed]
PHST- 2012/08/16 06:00 [medline]
PHST- 2013/05/25 00:00 [pmc-release]
AID - S0021-9258(20)50075-6 [pii]
AID - M112.339317 [pii]
AID - 10.1074/jbc.M112.339317 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 May 25;287(22):18330-41. doi: 10.1074/jbc.M112.339317. Epub 
      2012 Apr 4.