Rapamycin-induced inhibition of HTLV-I LTR activity is rescued by c-Myb.
BACKGROUND
Rapamycin is an immunosuppressive which represses translation of transcripts harbouring a polypyrimidine motif downstream of the mRNA cap site through the mammalian target of rapamycin complex. It inhibits the abnormal autologous proliferation of T-cell clones containing a transcriptionally active human T-lymphotropic virus, type I (HTLV-I) provirus, generated from infected subjects. We showed previously that this effect is independent of the polypyrimidine motifs in the viral long terminal repeat (LTR) R region suggesting that HTLV-I transcription, and not translation, is being affected. Here we studied whether rapamycin is having an effect on a specific transcription factor pathway. Further, we investigated whether mRNAs encoding transcription factors involved in HTLV-I transcriptional activation, specifically CREB, Ets and c-Myb, are implicated in the rapamycin-sensitivity of the HTLV-I LTR.


RESULTS
An in vitro analysis of the role of SRE- and NF-kappaB-mediated transcription highlighted the latter as rapamycin sensitive. Over-expression of c-Myb reversed the rapamycin effect.


CONCLUSIONS
The sensitivity of HTLV-I transcription to rapamycin may be effected through an NF-kappaB-pathway associated with the rapamycin-sensitive mTORC1 cellular signalling network.
Rose
Nicola J
NJ
Division of Retrovirology, National Institute for Biological Standards and Control, Blanche Lane, Potters Bar, Hertfordshire, UK. nrose@nibsc.ac.uk
Lever
Andrew M L
AM
D019677:Artificial Gene Fusion; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D017977:Deltaretrovirus; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D020079:Terminal Repeat Sequences / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
D016328:NF-kappa B; D020598:Proto-Oncogene Proteins c-myb; D015500:Chloramphenicol O-Acetyltransferase; D020123:Sirolimus