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.
Highlights
Faithful duplication of the genetic content of cells and proper segregation into two daughter cells are two highly regulated and distinct processes
Centrosome amplification, which results in aneuploidy, is seen in a large number of cancers, including adult T cell lymphoma, and the human T cell lymphotrophic virus Type 1 (HTLV-1) transactivator Tax plays a critical role in this process
(page number not for citation purposes) http://www.retrovirology.com/content/3/1/50 by multinucleated T cells. This suggests that aneugenic damage is an early phenomenon in adult T cell leukemia (ATL) development; how aneugenic damage contributes to malignant transformation is still not known
Summary
Faithful duplication of the genetic content of cells and proper segregation into two daughter cells are two highly regulated and distinct processes. Dysregulation of either the cell cycle or centrosome duplication can result in major genetic alterations and cancer [1,2,3]. Alterations in centrosome duplication and the resulting aneuploidy are observed in a significant number of cancers. There are several possible mechanisms of centrosome amplification, including: (i) centrosome duplication more than once in a cell cycle; (ii) failure to undergo cytokinesis resulting in doubling of the genome [6]; and improper splitting, or fragmentation, of centrosomes in the M phase due to DNA damage [8]. Some of the common genetic alterations in cancer associated with centrosome amplification include inactivation of p53, over-expression of Cyclin E [6], and mutation of BRCA1 [6,10]. Similar to HPV E6, the KSHV latency associated nuclear antigen (LANA) binds to p53 and inhibits the ability of p53 to transactivate cellular genes resulting in abnormal centrosomes, multinuclear cells, and other genomic abnormalities [17]
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