PMID- 11861406
OWN - NLM
STAT- MEDLINE
DCOM- 20020327
LR  - 20220317
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 62
IP  - 4
DP  - 2002 Feb 15
TI  - Activation of nuclear factor kappaB in radioresistance of TP53-inactive human 
      keratinocytes.
PG  - 1213-21
AB  - Many tumors show a mutant or inactive tumor suppressor p53 (TP53) status, and 
      TP53 in the tumor-carrying human papillomavirus (HPV) may be dysfunctional 
      because of inhibition by the viral protein HPV E6. Molecular mechanisms 
      underlying radiation responses and the radiation-induced resistant phenotype in 
      the TP53-inactive tumor have not been well investigated. In the present study, 
      using a human keratinocyte line (HK18) with TP53 inhibited by HPV18 infection, we 
      demonstrated that nuclear factor (NF)-kappaB is responsible for a major portion 
      of the radioresistance observed in a cell population (HK18-IR) derived from HK18 
      cells by fractionated ionizing radiation (FIR; 2 Gy/fraction; total dose, 60 Gy). 
      HK18-IR cells showed increased clonogenic radioresistance [dose-modifying factor 
      (DMF), 1.47], reduced apoptotic response, and a shortened radiation-induced 
      growth delay. Both DNA-binding and reporter transcriptional activity of 
      NF-kappaB, but not of TP53, were activated in HK18-IR cells compared with the 
      parental HK18 cells; this activation was observed both before and after a single 
      dose of 5 Gy. To determine target genes responsive to NF-kappaB activation, DNA 
      microarray profiles for 588 genes were matched in HK18-IR cells compared with 
      those in HK18 cells; the paired comparisons were made for basal levels before 
      irradiation or for levels 24 h after 5 Gy. For 25 genes, a 2- to 5-fold 
      up-regulation in HK18-IR cells relative to HK18 cells was similar when 
      comparisons were made for basal levels or for levels after irradiation. Included 
      in the approximately 4% of genes activated in HK18-IR cells, were six genes 
      (Cyclin B1, Cyclin D1, HIAP, BAG-1, TTF, and fibronectin) putatively linked to 
      NF-kappaB regulation. We then measured the expression of this group of 
      FIR-regulated genes in HK18-IR cells expressing a dominant-negative mutant 
      IkappaB (mIkappaB) that inhibited NF-kappaB activation. Clonogenic 
      radioresistance was reduced greatly in the mIkappaB transfectants (DMF, 1.18 and 
      1.10, respectively, at 10% and 1% of isosurvival for mIkappaB transfectants 
      compared with 1.47 and 1.45, respectively, for vector control transfectants). 
      Expressions of Cyclin B1, Cyclin D1, and HIAP were down-regulated by the 
      inhibition of NF-kappaB. These results suggest that transcription of NF-kappaB 
      and a group of NF-kappaB target genes are involved in radioresistance in 
      FIR-treated tumor cells with inactive TP53.
FAU - Chen, Xufeng
AU  - Chen X
AD  - Department of Cell and Tumor Biology, Beckman Research Institute, City of Hope 
      National Medical Center, Duarte, California 91010, USA.
FAU - Shen, Binghui
AU  - Shen B
FAU - Xia, Liqun
AU  - Xia L
FAU - Khaletzkiy, Alexander
AU  - Khaletzkiy A
FAU - Chu, David
AU  - Chu D
FAU - Wong, Jeffrey Y C
AU  - Wong JY
FAU - Li, Jian-Jian
AU  - Li JJ
LA  - eng
GR  - CA85344/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Apoptosis/genetics
MH  - Cell Cycle/genetics
MH  - Gene Expression Regulation
MH  - Humans
MH  - I-kappa B Proteins/genetics
MH  - Keratinocytes/cytology/physiology/*radiation effects
MH  - NF-kappa B/biosynthesis/genetics/*physiology
MH  - Radiation Tolerance/*genetics
MH  - Transcriptional Activation/radiation effects
MH  - Transfection
MH  - Tumor Suppressor Protein p53/*physiology
MH  - Up-Regulation/radiation effects
EDAT- 2002/02/28 10:00
MHDA- 2002/03/28 10:01
CRDT- 2002/02/28 10:00
PHST- 2002/02/28 10:00 [pubmed]
PHST- 2002/03/28 10:01 [medline]
PHST- 2002/02/28 10:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2002 Feb 15;62(4):1213-21.