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  • Cancer patients may develop cachexia a deleterious wasting s


    Cancer patients may develop cachexia, a deleterious wasting syndrome that is associated with muscle atrophy and has an impact on the well-being of patients and on the response to the treatment. Indeed, cachexia is a devastating and often irreversible syndrome observed in up to 80% of cancer patients [20]. Most importantly, cachexia has been shown to be responsible for the death of 20% of all cancer patients [21], [22]. In mice, defects in skeletal muscle regeneration and satellite cell differentiation due to a deregulation of Pax7 expression have been demonstrated to contribute to cancer cachexia [23]. Indeed, the efficiency of muscle mass and its maintenance in cancer patients has been used as an independent predictor of mortality in some cancers [24], [25] and should be closely monitored. To date, no data are available regarding the effect of a loss of CRL activity on muscle cell differentiation and the effect of MLN4924 on muscle cells. Given the emerging role of CRL substrate adaptors in muscle development and disease [11], we decided to address the function of CRL in myogenesis and myotube formation by using MLN4924 and siRNA experiments. Our data revealed, for the first time, that CRL activity is required for myoblast differentiation and for the commitment of the skeletal muscle stem plerixafor receptor into the myogenic differentiation program. Our data highlight that MLN4924, a CRL activity inhibitor used currently as a potential cancer therapy, has potentially negative side effects on muscle cell differentiation through, in part, the regulation of myogenin expression. Given the systemic delivery of MLN4924 in cancer patients during clinical trials [18], [19], our results suggest the necessity to closely monitor skeletal muscle mass and muscle regeneration in treated patients.
    Material and Methods
    Acknowledgments Funding for this project was provided by an NIH-NHLBI K99/R00 and R01 grant to S.L. (HL107744, HL128457) and supported by a Philippe Foundation grant to J.B. and a UC San Diego Ledell Family Undergraduate Research Scholarship to P.S.
    Introduction Among the various post-translational modifications made to proteins, ubiquitination emerges as one of the best studied, affecting the spatiotemporal regulation of numerous proteins involved in key cellular process, such as the cell cycle [1], [2], [3], [4], transcription [5], [6], and apoptosis [7], among other functions. Ubiquitination involves the conjugation of ubiquitin (Ub) to a lysine residue on the substrate, and this mostly occurs via an E1, E2, and E3 enzymatic cascade [8], [9]. The E1-activating enzyme modifies and covalently links with the Ub molecule, binds to an E2-conjugating enzyme, and transfers the Ub to the E2 active-site cysteine residue. The E3‐ubiquitin ligases are then responsible for the final step of the cascade, where they bind specifically to the target and approximate the target with the E2~Ub conjugate to transfer Ub to the target lysine residue. Ubiquitination can occur on a single (monoubiquitination) or several (multiubiquitination) lysine residues, or the same lysine residue can be subjected to several rounds of Ub conjugation (polyubiquitination). Ub bonds within polyUb chains are formed through 1 of 7 lysine residues in Ub, and the types of chains that form will dictate how the protein will be processed by the cell. For example, polyUb chains predominantly composed of Ub K48- or K29-links will target a protein for proteasomal degradation, whereas other Ub chains (K63-linked Ub chains, for example) regulate kinase activation, DNA damage, signal transduction, and endocytosis [10], [11]. E2–E3 enzyme combinations differentially affect ubiquitination outcomes [12]. Moreover, E3 enzymes have defined activities and bind selectively to substrates. Indeed, deregulation of E3 ligases can affect cell growth signals, DNA repair and result in various malignancies [13]. Among the various E3 ligases identified, RING finger-type E3 ligases are the most abundant. The E3 RING domain requires the action of a specific E2 to transfer Ub to the substrate or other Ub molecules (free polyUb chains); our study adds new insight into how one of these RING-type E3 ligases selectively catalyzes the transfer of Ub to the appropriate substrate or Ub itself.