PMID- 19838207
OWN - NLM
STAT- MEDLINE
DCOM- 20100212
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 29
IP  - 3
DP  - 2010 Jan 21
TI  - Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB 
      activity in hypoxic tumor cells.
PG  - 356-67
LID - 10.1038/onc.2009.342 [doi]
AB  - The expression of hypoxia-inducible factor-1 (HIF-1) correlates with poor 
      clinical outcomes and confers resistance to the apoptosis of the tumor cells that 
      are exposed to hypoxia. Presently, the mechanism underlying this phenomenon is 
      poorly understood. In this study we provide evidence that transglutaminase 2 
      (TG2), an enzyme that catalyses protein crosslinking reactions, is a 
      transcriptional target of HIF-1 to enhance the survival of hypoxic cells. We 
      found that hypoxia induces TG2 expression through an HIF-1 dependent pathway and 
      concurrently activates intracellular TG2. The hypoxic cells overexpressing TG2 
      showed resistance to apoptosis. Conversely, the hypoxic cells treated with either 
      TG2 inhibitor or small interfering RNA (siRNA) became sensitive to apoptosis. 
      Activation of TG2 in response to hypoxic stress inhibited caspase-3 activity by 
      forming crosslinked multimer, resulting in insoluble aggregates. TG2 also 
      activates nuclear factor (NF)-kappaB pathway after hypoxic stress, and thereby 
      induces the expression of cellular inhibitor of apoptosis 2. The anti-apoptotic 
      role of TG2 was further confirmed in vivo using xenografts in athymic mice. Our 
      results indicate that TG2 is an anti-apoptotic mediator of HIF-1 through 
      modulating both apoptosis and survival pathways and may confer a selective growth 
      advantage to tumor cells. These findings suggest that the inhibition of TG2 may 
      offer a novel strategy for anticancer therapy.
FAU - Jang, G-Y
AU  - Jang GY
AD  - Department of Biochemistry and Molecular Biology/Aging and Apoptosis Research 
      Center (AARC), Seoul National University College of Medicine, Seoul 110-799, 
      Korea.
FAU - Jeon, J-H
AU  - Jeon JH
FAU - Cho, S-Y
AU  - Cho SY
FAU - Shin, D-M
AU  - Shin DM
FAU - Kim, C-W
AU  - Kim CW
FAU - Jeong, E M
AU  - Jeong EM
FAU - Bae, H C
AU  - Bae HC
FAU - Kim, T W
AU  - Kim TW
FAU - Lee, S-H
AU  - Lee SH
FAU - Choi, Y
AU  - Choi Y
FAU - Lee, D-S
AU  - Lee DS
FAU - Park, S-C
AU  - Park SC
FAU - Kim, I-G
AU  - Kim IG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091019
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2)
RN  - EC 2.3.2.13 (Transglutaminases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Caspase 3/*metabolism
MH  - Cell Hypoxia
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - GTP-Binding Proteins/chemistry/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - HeLa Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - NF-kappa B/*metabolism
MH  - Neoplasms/genetics/metabolism/pathology
MH  - Neoplasms, Experimental/genetics/metabolism/pathology
MH  - Protein Glutamine gamma Glutamyltransferase 2
MH  - Protein Multimerization
MH  - RNA Interference
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transglutaminases/chemistry/genetics/*metabolism
MH  - Transplantation, Heterologous
MH  - Tumor Burden
EDAT- 2009/10/20 06:00
MHDA- 2010/02/13 06:00
CRDT- 2009/10/20 06:00
PHST- 2009/10/20 06:00 [entrez]
PHST- 2009/10/20 06:00 [pubmed]
PHST- 2010/02/13 06:00 [medline]
AID - onc2009342 [pii]
AID - 10.1038/onc.2009.342 [doi]
PST - ppublish
SO  - Oncogene. 2010 Jan 21;29(3):356-67. doi: 10.1038/onc.2009.342. Epub 2009 Oct 19.