Nuclear factor-kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein.
Sustained proliferation of cancer cells requires telomerase to maintain telomeres that regulate chromosomal stability and cellular mitosis. Expression of human telomerase reverse transcriptase (hTERT) catalytic subunit, which modulates telomerase activity, is regulated at both the transcriptional level and via phosphorylation by Akt kinase. Moreover, nuclear localization of hTERT is required to promote elongation of telomere sequences. In this study, we show for the first time that hTERT protein interacts directly with nuclear factor (NF)-kappaB p65 in MM.1S cells. Importantly, tumor necrosis factor alpha (TNFalpha) modulates telomerase activity by inducing translocation from the cytoplasm to the nucleus of hTERT protein bound to NF-kappaB p65. Conversely, a specific IkappaB kinase (IKK) inhibitor PS-1145, and a specific NF-kappaB nuclear translocation inhibitor SN-50, both block TNFalpha-induced hTERT nuclear translocation. These studies suggest that NF-kappaB p65 plays a pivotal role in regulating telomerase by modulating its nuclear translocation.
Akiyama
Masaharu
M
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Hideshima
Teru
T
Hayashi
Toshiaki
T
Tai
Yu-Tzu
YT
Mitsiades
Constantine S
CS
Mitsiades
Nicholas
N
Chauhan
Dharminder
D
Richardson
Paul
P
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D004268:DNA-Binding Proteins; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D019098:Telomerase / Q000187:drug effects / Q000378:metabolism*; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019098:Telomerase