Submitted June 28, 2006
Accepted February 28, 2007
Resistance to TGF-
1 correlated with aberrant expression of TGF- receptor II in human B-cell lymphoma cell lines
Gang Chen, Paritosh Ghosh*, Hiroshi Osawa, Carl Y. Sasaki, Louis Rezanka, Jiandong Yang, Thomas J. O'Farrell, and Dan L. Longo
Lymphocyte Cell Biology Unit, Laboratory of Immunology, National Institute on Aging, NIH, Baltimore, MD
Laboratory of Genetics, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MD
* Corresponding author; email: ghoshp{at}grc.nia.nih.gov.
Resistance to TGF-
1-mediated growth suppression in tumor cells is often associated with the functional loss of TGF- receptors. Here we describe two B cell lymphoma cell lines (DB and RL) that differ in their sensitivity to TGF- mediated growth suppression. The TGF-1-resistant cell line DB lacked functional TGF- receptor II (TRII) in contrast to the TGF-1-responsive cell line RL, whereas both cell lines had comparable levels of receptor I (TRI). Lack of functional TRII was correlated with the lack of TGF-1-induced nuclear translocation of phospho-Smad3 and Smad2, the lack of nuclear expression of p21Cip1/WAF1 and the down regulation of c-Myc in DB cells. Transfection of wild type, but not a c-terminally truncated form of TRII rendered the DB cell line responsive to TGF-1-mediated growth suppression. Analysis of the TRII gene in DB cells revealed the absence of TRII message, which was reversed upon 5'-azacytidine treatment, indicating that the promoter methylation might be the cause of gene silencing. Promoter analysis revealed the CpG methylations at -25 and -140 that were correlated with the gene silencing. These data suggested that promoter methylation plays an important role in TRII gene silencing and subsequent development of TGF-1 resistant phenotype by some B-cell lymphoma cells.
