As the second most common hematologic neoplasm, multiple myeloma (MM) accounts for 1% of all cancers in Europe. Chromosomal instability, genetic heterogeneity and slow, but persistent, progression are main characteristics of this malignancy. Although MM remains an incurable disease, therapy response rates and progression free survival have significantly improved within the last decade – an achievement mainly owed the introduction of proteasome inhibitors. To warrant balanced metabolism and gene transcription as well as controlled cellular proliferation, the ubiquitin proteasome system (UPS) implies numerous highly conserved processes, which regulate stability, turnover and function of proteins. Key members of this system are the 26S proteasome, able to recognize and degrade ubiquitin-bound proteins, the ubiquitin ligases (E3), which catalyze the covalent linkage of proteins and ubiquitin molecules, and the deubiquitinating enzymes (DUBs). DUBs hydrolyze the bonds between ubiquitin molecules and proteins, to rescue their substrates from degradation or to impart them with a new function. Despite the effectiveness of proteasome inhibitors in the treatment of MM, the underlying deregulated UPS events have remained largely unknown. In search for potential candidates, analysis of comparative genomic hybridization arrays revealed the loss of the Usp24 gene locus, encoding for the orphan DUB USP24, in 25% of MM patient samples. In an unbiased mass spectrometric screen WWP2 (WW domain containing E3 ubiquitin protein ligase 2) was identified as a binding partner of USP24 – an E3 ligase, known to interact with members of the TGF-beta system. Hence, this study characterized the connection between the TGF-beta pathway and USP24, revealing SMAD3 as a critical interaction partner of this DUB. The receptor-activated SMAD3 complies an essential function as a cytoplasmic mediator of TGF-beta signaling, responsible for the initiation of transcriptional responses. Presented experiments show enhanced SMAD3 activation and thus deregulation of TGF-beta signaling in USP24 deficient cells – representative for 25% of MM patients and in accordance with the fact, that the TGF-beta system is deregulated in this cancer. Hence, this study defined USP24 as a UPS member, that is involved in the regulation of the TGF-beta signaling pathway with a potential role as a tumor suppressor.
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As the second most common hematologic neoplasm, multiple myeloma (MM) accounts for 1% of all cancers in Europe. Chromosomal instability, genetic heterogeneity and slow, but persistent, progression are main characteristics of this malignancy. Although MM remains an incurable disease, therapy response rates and progression free survival have significantly improved within the last decade – an achievement mainly owed the introduction of proteasome inhibitors. To warrant balanced metabolism and gene...
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