A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions.
The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.
Laboratory of Molecular Virology, Department of Biological Sciences, Southern Methodist University, 334-DLS, 6501 Airline Drive, Dallas, TX 75275-0376. rharrod@mail.smu.edu.
Soumya
S
Awasthi
Anima
A
Sharma
Kasuen
K
Wong
Junyu
J
Zhang
Elizabeth F
EF
Matlock
Lowery
L
Rogers
Pamela
P
Motloch
Shigeki
S
Takemoto
Hirokuni
H
Taguchi
Michael D
MD
Cole
Bernhard
B
Lüscher
Oliver
O
Dittrich
Hideaki
H
Tagami
Yoshihiro
Y
Nakatani
Monnie
M
McGee
Anne-Marie
AM
Girard
Luke
L
Gaughan
Craig N
CN
Robson
Raymond J
RJ
Monnat
Robert
R
Harrod
D000123:Acetyltransferases / Q000032:analysis / Q000378:metabolism*; D017398:Alternative Splicing; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000821:virology; D002471:Cell Transformation, Neoplastic; D042002:Chromatin Assembly and Disassembly; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics*; D020869:Gene Expression Profiling; D051548:Histone Acetyltransferases; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000821:virology*; D000074443:Lysine Acetyltransferase 5; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012191:Retroviridae Proteins; C072814:tof protein, Human T-lymphotropic virus 1; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5