Molecular functions of the TRE17/ubiquitin-specific protease 6 (USP6) oncogene: A novel activator of NF-kappa B .

摘要

Aneurysmal bone cyst (ABC) is an aggressive pediatric bone tumor that is highly inflammatory, highly vascularized, and causes massive bone destruction. Until recently, ABCs were thought to be reactive lesions caused by a local vascular disturbance. However, recent chromosomal analyses suggest a neoplastic origin. In 63% of ABCs, a translocation event involving TRE17 and promoters of highly active genes occurs, leading to high TRE17 expression in these tumors. TRE17 encodes a ubiquitin-specific protease (USP), however the mechanism by which it contributes to the formation of ABC is unknown. Recent work from our laboratory has shown that TRE17 induces the expression of a variety of matrix metalloproteases (MMPs). The studies outlined in Chapter 3 reveal that TRE17 is sufficient to induce the production of inflammatory cytokines. TRE17-induced MMP and cytokine production may contribute to the bone degradation and inflammation observed in ABCs. Chapter 3 further shows that induction of these factors depends on TRE17's USP activity, and is mediated though NFkappaB. The data in Chapter 4 elucidate the mechanism of activation of NFkappaB by TRE17.;NFkappaB comprises a family of transcription factors that have been divided into canonical and non-canonical pathways. Here we show that TRE17 induces activation of the canonical p65/p50 NFkappaB, through an atypical mechanism that does not entail degradation of Inhibitor of NFkappaB (IkappaB). TRE17 associates with a unique IkappaB kinase (IKK) complex containing IKKalpha and IKKbeta, but lacking the IKKgamma/NEMO subunit that is normally required for the canonical pathway. Using siRNAs targeting IKKalpha or IKKbeta, we demonstrate that both kinases are essential for full activation of NFkappaB by TRE17. IKKalpha-associated kinase activity is enhanced in cells expressing wild type TRE17, but not a USP-inactive mutant. We further show that TRE17 enhances IKK activity in vivo as cells expressing TRE17 exhibit enhanced phosphorylation of p65 at serine 536, a modification that is associated with its nuclear accumulation and potentiation of transcriptional activity. We further show that TRE17 regulates activation of NFkappaB by physiological stimuli. This work identifies TRE17 as the first USP to induce activation of the NFkappaB pathway, and delineates a unique signaling mechanism for its activation.