Rapamycin-induced inhibition of HTLV-I LTR activity is rescued by c-Myb

• Published in: Retrovirology Vol. 4; no. 1; p. 24
• Main Authors: Rose, Nicola J, Lever, Andrew ML
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.04.2007; BioMed Central; BMC
• Subjects: Artificial Gene Fusion; Chloramphenicol O-Acetyltransferase - biosynthesis; Deltaretrovirus; DNA binding proteins; Dosage and administration; Genes, Reporter; Genetic aspects; HTLV-I (Virus); Human T-lymphotropic virus 1 - drug effects; Human T-lymphotropic virus 1 - genetics; Human T-lymphotropic virus 1 - physiology; Humans; NF-kappa B - antagonists & inhibitors; Proto-Oncogene Proteins c-myb - physiology; Rapamycin; Sirolimus - pharmacology; T cell proliferation; Terminal Repeat Sequences - drug effects; Transcription, Genetic - drug effects; United Kingdom
• ISSN: 1742-4690; 1742-4690
• DOI: 10.1186/1742-4690-4-24

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. 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. 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.