Human T Lymphotropic Virus Type 1 protein Tax reduces histone levels.
BACKGROUND
Human T-Lymphotropic Virus Type-1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATLL). The virally encoded Tax protein is thought to be necessary and sufficient for T-cell leukemogenesis. Tax promotes inappropriate cellular proliferation, represses multiple DNA repair mechanisms, deregulates cell cycle checkpoints, and induces genomic instability. All of these Tax effects are thought to cooperate in the development of ATLL.


RESULTS
In this study, we demonstrate that histone protein levels are reduced in HTLV-1 infected T-cell lines (HuT102, SLB-1 and C81) relative to uninfected T-cell lines (CEM, Jurkat and Molt4), while the relative amount of DNA per haploid complement is unaffected. In addition, we show that replication-dependent core and linker histone transcript levels are reduced in HTLV-1 infected T-cell lines. Furthermore, we show that Tax expression in Jurkat cells is sufficient for reduction of replication-dependent histone transcript levels.


CONCLUSIONS
These results demonstrate that Tax disrupts the proper regulation of replication-dependent histone gene expression. Further, our findings suggest that HTLV-1 infection uncouples replication-dependent histone gene expression and DNA replication, allowing the depletion of histone proteins with cell division. Histone proteins are involved in the regulation of all metabolic processes involving DNA including transcription, replication, repair and recombination. This study provides a previously unidentified mechanism by which Tax may directly induce chromosomal instability and deregulate gene expression through reduced histone levels.
Bogenberger
James M
JM
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, USA. jimbog@simla.colostate.edu
Laybourn
Paul J
PJ
D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000096:biosynthesis* / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014162:Transfection
D016356:Gene Products, tax; D006657:Histones; D012333:RNA, Messenger; D004247:DNA