Analyses of retinoic or arsenic induced pml/rara degradation yields new insights into pml nuclear body formation and ligand-triggered nuclear receptor activation

Jun Zhu MD PhD, V Lallemand-Breitenbach PhD, H de The MD PhD

CNRS UPR 9051 Hôpital St. Louis PARIS France.

Aims & methods: Expression of the PML/RARa fusion protein underlies the pathogenesis of acute promyelocytic leukemia (APL) as well as its clinical response to retinoic acid and arsenic trioxide. We have previously shown that an unexpected similarity between these two agents is to induce the catabolism of the fusion protein. Results: A detailed analysis of the pathways involved in PML/RARa degradation will be presented. Retinoic acid targets the RARa moiety of the fusion protein to the proteasome, most likely through the interaction of ligand-activated AF2 with the 19S component SUG-1. Arsenic targets the PML moiety of the fusion to the 11S proteasome component, through the sumolation of lysine 160. How oncogene degradation relates to disease remission will be discussed in the context of single or dual therapies. Conclusions: Analysis of the molecular pathways involved in PML degradation by arsenic has allowed the determination of the exact contribution of PML sumolation to PML nuclear body organization. Contrary to previous proposal, it appears that PML sumolation is not required for arsenic-induced PML targeting to the nuclear matrix, but required for both maturation and recruitment of other proteins, including proteasome components, onto these structures. Similarly, ligand-induced nuclear receptor degradation has shed a new light on the relations between proteasome activation and transcriptional activation

KEY WORDS: leukemia, proteasome, retinoic acid, arsenic, therapy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.