PMID- 10490642
OWN - NLM
STAT- MEDLINE
DCOM- 20000203
LR  - 20190816
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 10
DP  - 1999 Oct
TI  - Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with 
      the GADD34 and hSNF5/INI1 proteins.
PG  - 7050-60
AB  - One of the most common chromosomal abnormalities in acute leukemia is a
      reciprocal translocation involving the HRX gene (also called MLL, ALL-1, or HTRX)
      at chromosomal locus 11q23, resulting in the formation of HRX fusion proteins.
      Using the yeast two-hybrid system and human cell culture coimmunoprecipitation
      experiments, we show here that HRX proteins interact directly with the GADD34
      protein. We have found that transfected cells overexpressing GADD34 display a
      significant increase in apoptosis after treatment with ionizing radiation,
      indicating that GADD34 expression not only correlates with apoptosis but also can
      enhance apoptosis. The amino-terminal third of the GADD34 protein was necessary
      for this observed increase in apoptosis. Furthermore, coexpression of three
      different HRX fusion proteins (HRX-ENL, HRX-AF9, and HRX-ELL) had an
      anti-apoptotic effect, abrogating GADD34-induced apoptosis. In contrast,
      expression of wild-type HRX gave rise to an increase in apoptosis. The difference
      observed here between wild-type HRX and the leukemic HRX fusion proteins suggests
      that inhibition of GADD34-mediated apoptosis may be important to leukemogenesis. 
      We also show here that GADD34 binds the human SNF5/INI1 protein, a member of the 
      SNF/SWI complex that can remodel chromatin and activate transcription. These
      studies demonstrate, for the first time, a gain of function for leukemic HRX
      fusion proteins compared to wild-type protein. We propose that the role of HRX
      fusion proteins as negative regulators of post-DNA-damage-induced apoptosis is
      important to leukemia progression.
FAU - Adler, H T
AU  - Adler HT
AD  - VA Puget Sound Health Care System, Seattle, Washington 98108, USA.
FAU - Chinery, R
AU  - Chinery R
FAU - Wu, D Y
AU  - Wu DY
FAU - Kussick, S J
AU  - Kussick SJ
FAU - Payne, J M
AU  - Payne JM
FAU - Fornace, A J Jr
AU  - Fornace AJ Jr
FAU - Tkachuk, D C
AU  - Tkachuk DC
LA  - eng
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - CA 68485/CA/NCI NIH HHS/United States
GR  - CA73969/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromosomal Proteins, Non-Histone)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (KMT2A protein, human)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Proteins)
RN  - 0 (SMARCB1 Protein)
RN  - 0 (SMARCB1 protein, human)
RN  - 0 (Transcription Factors)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 3.1.3.16 (PPP1R15A protein, human)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
SB  - IM
MH  - Antigens, Differentiation
MH  - *Apoptosis
MH  - Binding Sites
MH  - Cell Cycle Proteins
MH  - Chromosomal Proteins, Non-Histone
MH  - DNA-Binding Proteins/*metabolism
MH  - Gamma Rays
MH  - Gene Expression Regulation, Neoplastic/radiation effects
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Leukemia/*metabolism
MH  - Mutation
MH  - Myeloid-Lymphoid Leukemia Protein
MH  - Oncogene Proteins, Fusion/*metabolism
MH  - Protein Binding
MH  - Protein Phosphatase 1
MH  - Proteins/*metabolism
MH  - *Proto-Oncogenes
MH  - SMARCB1 Protein
MH  - Sequence Deletion
MH  - *Transcription Factors
MH  - Tumor Cells, Cultured
MH  - Two-Hybrid System Techniques
PMC - PMC84700
EDAT- 1999/09/22 09:00
MHDA- 2001/03/28 10:01
CRDT- 1999/09/22 09:00
PHST- 1999/09/22 09:00 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/09/22 09:00 [entrez]
AID - 10.1128/mcb.19.10.7050 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Oct;19(10):7050-60. doi: 10.1128/mcb.19.10.7050.