Molecular mechanisms of cellular transformation by HTLV-1 Tax.
The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.
Grassmann
Ralph
R
Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schlossgarten 4, Germany. Ralph.Grassmann@viro.med.uni-erlangen.de
Aboud
Mordechai
M
Jeang
Kuan-Teh
KT
D000818:Animals; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000235:genetics; D004249:DNA Damage; D016356:Gene Products, tax / Q000235:genetics* / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000821:virology; D015533:Transcriptional Activation; D014779:Virus Replication
D016207:Cytokines; D016356:Gene Products, tax; D011956:Receptors, Cell Surface