Carcinogenesis Advance Access published online on June 10, 2004
Carcinogenesis, doi:10.1093/carcin/bgh198
© 2004 by Oxford University Press
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1 Gene Regulation Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick, Maryland, 21702
* To whom correspondence should be addressed. E-mail: huji{at}ncifcrf.gov.
NF- Key Words:
p65, phosphorylation, transformation, JB6 cells
Revised April 1, 2004
Accepted May 25, 2004
CARCINOGENESIS
Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-
B activation and transformation in resistant JB6 cells
2 Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
3 The Department of Pathogenic Biochemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 c, Toyama 930-0194, Japan
Abstract 
B activation is required for TNF-
-induced transformation of JB6 mouse epidermal cells. Deficient activation of p65 contributes to the lack of NF-B activation in transformation resistant (P-) cells. We hypothesized that the differential NF-B activation involves differential p65 phosphorylation arising from enzyme activity differences. Here we show that TNF- induces greater ERK-dependent p65 phosphorylation at S536 in transformation sensitive (P+) cells than in P- cells. Our results establish that limited ERK content contributes to a low IKK
level, in turn resulting in insufficient p65 phosphorylation at S536 upon TNF- stimulation in P- cells. Phosphorylation of p65 at S536 appears to play a role in TNF--induced p65 DNA binding and recruitment of p300 to the p65 complex as well as in release of p65 bound to HDAC 1 and 3. Blocking p65 phosphorylation at S536, but not at S276 or S529, abolishes p65 transactivational activity. Over-expression of p65 but not p65 phosphorylation mutant (S536A) in transformation resistant P- cells renders these cells sensitive to TNF- induced transformation. Over-expression of p65 phosphorylation mimics p65-S536D or p65-S536E in P- cells also rescues the transformation response. These findings provide direct evidence that phosphorylation of p65 at S536 is required for TNF- induced NF-B activation in the JB6 transformation model. The lack of NF-B activation seen in P- cells can be attributed to an insufficient level of p65 phosphorylation on S536 that arises from insufficient IKK that in turn arises from insufficient ERK. Thus, p65 phosphorylation at S536 offers a potential molecular target for cancer prevention.
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