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Genomic instability is a hallmark of many cancers; however, the molecular etiology of chromosomal dysregulation is not well understood. The human T-cell leukemia virus type-1 (HTLV-1) oncoprotein Tax activates NF-κB-signaling and induces DNA-damage and aberrant chromosomal segregation through diverse mechanisms which contribute to viral carcinogenesis. Intriguingly, Stathmin/oncoprotein-18 (Op-18) depolymerizes tubulin and interacts with the p65 subunit and functions as a cofactor for NF-κB-dependent transactivation. We thus hypothesized that the dissociation of p65-Stathmin/Op-18 complexes by Tax could lead to the catastrophic destabilization of microtubule (MT) spindle fibers during mitosis and provide a novel mechanistic link between NF-κB-signaling and genomic instability. Here we report that the inhibition of Stathmin expression by the retroviral latency protein, p30, or knockdown with siRNA-stathmin, dampens Tax-mediated NF-κB transactivation and counters Tax-induced genomic instability and cytotoxicity. The Tax-G148V mutant, defective for NF-κB activation, exhibited reduced p65-Stathmin binding and diminished genomic instability and cytotoxicity. Dominant-negative inhibitors of NF-κB also prevented Tax-induced multinucleation and apoptosis. Moreover, cell clones containing the infectious HTLV-1 ACH. p30 mutant provirus, impaired for p30 production, exhibited increased multinucleation and the accumulation of cytoplasmic tubulin aggregates following nocodozole-treatment. These findings allude to a mechanism whereby NF-κB-signaling regulates tubulin dynamics and mitotic instability through the modulation of p65-Stathmin/Op-18 interactions, and support the notion that p30 enhances the survival of Tax-expressing HTLV-1-transformed cells.
This article was published in the following journal.
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A ubiquitous phosphoprotein that serves as an intracellular substrate for a variety of SIGNAL TRANSDUCTION PATHWAYS. PHOSPHORYLATION of stathmin occurs during CELL CYCLE progression, and stathmin functions as a microtubule-destabilizing protein that promotes MICROTUBULE depolymerization during INTERPHASE and late MITOSIS. Stathmin is expressed at very high levels in a variety of human CANCERS.
A strain of Murine leukemia virus (LEUKEMIA VIRUS, MURINE) producing leukemia of the reticulum-cell type with massive infiltration of liver, spleen, and bone marrow. It infects DBA/2 and Swiss mice.
A genus in the family RETROVIRIDAE consisting of exogenous horizontally-transmitted viruses found in a few groups of mammals. Infections caused by these viruses include human B- or adult T-cell leukemia/lymphoma (LEUKEMIA-LYMPHOMA, T-CELL, ACUTE, HTLV-I-ASSOCIATED), and bovine leukemia (ENZOOTIC BOVINE LEUKOSIS). The type species is LEUKEMIA VIRUS, BOVINE.
A replication-defective strain of Murine leukemia virus (LEUKEMIA VIRUS, MURINE) capable of transforming lymphoid cells and producing a rapidly progressing lymphoid leukemia after superinfection with FRIEND MURINE LEUKEMIA VIRUS; MOLONEY MURINE LEUKEMIA VIRUS; or RAUSCHER VIRUS.
A strain of PRIMATE T-LYMPHOTROPIC VIRUS 1 isolated from mature T4 cells in patients with T-lymphoproliferation malignancies. It causes adult T-cell leukemia (LEUKEMIA-LYMPHOMA, T-CELL, ACUTE, HTLV-I-ASSOCIATED), T-cell lymphoma (LYMPHOMA, T-CELL), and is involved in mycosis fungoides, SEZARY SYNDROME and tropical spastic paraparesis (PARAPARESIS, TROPICAL SPASTIC).