The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-κB p65^RelA-Stathmin complexes and causes...

Area of Science:

• Oncology
• Virology
• Cell Biology

Background:

• Genomic instability is a hallmark of cancer, but its molecular causes, particularly chromosomal dysregulation, remain unclear.
• The human T-cell leukemia virus type-1 (HTLV-1) oncoprotein Tax contributes to viral carcinogenesis by activating NF-κB signaling, inducing DNA damage, and causing aberrant chromosomal segregation.
• Stathmin/oncoprotein-18 (Op-18) interacts with NF-κB p65RelA, influencing NF-κB-dependent transactivation and depolymerizing tubulin.

Purpose of the Study:

• To investigate the hypothesis that Tax-induced dissociation of p65RelA-Stathmin complexes destabilizes mitotic spindle fibers, linking NF-κB signaling to genomic instability.
• To explore the role of the HTLV-1 latency protein p30II in modulating Tax-mediated genomic instability and cytotoxicity.

Main Methods:

• Inhibition of Stathmin expression using retroviral p30II or siRNA-stathmin.
• Analysis of Tax-G148V mutant defective for NF-κB activation.
• Use of dominant-negative NF-κB inhibitors.
• Assessment of HTLV-1 ACH.p30II mutant provirus-containing cell clones.

Main Results:

• Inhibition of Stathmin (via p30II or siRNA) reduced Tax-mediated NF-κB transactivation, genomic instability, and cytotoxicity.
• The Tax-G148V mutant showed decreased p65RelA-Stathmin binding, reduced genomic instability, and cytotoxicity.
• Dominant-negative NF-κB inhibitors prevented Tax-induced multinucleation and apoptosis.
• HTLV-1 ACH.p30II mutant cells exhibited increased multinucleation and tubulin aggregates after nocodazole treatment.

Conclusions:

• NF-κB signaling regulates tubulin dynamics and mitotic instability through p65RelA-Stathmin interactions.
• p30II enhances the survival of Tax-expressing HTLV-1-transformed cells.
• These findings provide a novel mechanistic link between HTLV-1 Tax, NF-κB signaling, and genomic instability in viral carcinogenesis.