HTLV-1 Tax: centrosome amplification and cancer

Abstract

During interphase, each cell contains a single centrosome that acts as a microtubule organizing center for cellular functions in interphase and in mitosis. Centrosome amplification during the S phase of the cell cycle is a tightly regulated process to ensure that each daughter cell receives the proper complement of the genome. The controls that ensure that centrosomes are duplicated exactly once in the cell cycle are not well understood. In solid tumors and hematological malignancies, centrosome abnormalities resulting in aneuploidy is observed in the majority of cancers. These phenotypes are also observed in cancers induced by viruses, including adult T cell lymphoma which is caused by the human T cell lymphotrophic virus Type 1 (HTLV-1). Several reports have indicated that the HTLV-1 transactivator, Tax, is directly responsible for the centrosomal abnormalities observed in ATL cells. A recent paper in Nature Cell Biology by Ching et al. has shed some new light into how Tax may be inducing centrosome abnormalities. The authors demonstrated that 30% of ATL cells contained more than two centrosomes and expression of Tax alone induced supernumerary centrosomes. A cellular coiled-coil protein, Tax1BP2, was shown to interact with Tax and disruption of this interaction led to failure of Tax to induce centrosome amplification. Additionally, down-regulation of Tax1BP2 led to centrosome amplification. These results suggest that Tax1BP2 may be an important block to centrosome re-duplication that is observed in normal cells. Presently, a specific cellular protein that prevents centrosome re-duplication has not been identified. This paper has provided further insight into how Tax induces centrosome abnormalities that lead to ATL. Lastly, additional work on Tax1BP2 will also provide insight into how the cell suppresses centrosome re-duplication during the cell cycle and the role that Tax1BP2 plays in this important cellular pathway.

Figure 1

Role of Tax binding proteins in centrosomal abnormalities observed in ATL cells. (A) TaxBP181 (hsMad1). During interphase TaxBP181 (light blue) is localized to the nucleus (yellow) and some co-localize with Tax (green) in infected cells. During the transition to prophase (1) in normal cells, TaxBP181 localizes to the kinetochores of chromosomes and allows proper segregation. (2) In normal cells during anaphase and telophase, TaxBP181 localizes to the midbody and finally in newly formed progeny nuclei. (3) When Tax is expressed in ATL cells, TaxBP181 is translocated to the nucleus, allowing for chromosome missegregation, resulting in multinucleated cells (4). (B) RanBP1. During interphase, Tax (green) is found in the nucleus and a portion is co-localized with RanBP1 (purple) on centrosomes. Interaction of Tax with RanBP1 dysregulates the centrosome duplication pathway resulting in cells with two or more centrosomes following mitosis. (C) Tax1BP2. During interphase Tax (green) is expressed in the nucleus and a portion co-localizes with pericentrin (purple) in centrosomes. During S phase centrosomes are duplicated. However, the interaction of Tax with Tax1BP2 (yellow) disrupts the normal controls that prevent centrosome re-duplication resulting in cells with more than two centrosomes. During mitosis, supernumerary centrosomes are separated into two daughter cells resulting in a percentage of cells with two or more centrosomes.