title: Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization.
abstract: Skeletal muscle degeneration is a complication arising from a variety of chronic diseases including advanced cancer. Pro-inflammatory cytokine TNF-α plays a pivotal role in mediating cancer-related skeletal muscle degeneration. Here, we show a novel function for retinoblastoma protein (Rb), where Rb causes sarcomeric disorganization. In human skeletal muscle myotubes (HSMMs), up-regulation of cyclin-dependent kinase 4 (CDK4) and concomitant phosphorylation of Rb was induced by TNF-α treatment, resulting in the translocation of phosphorylated Rb to the cytoplasm. Moreover, induced expression of the nuclear exporting signal (NES)-fused form of Rb caused disruption of sarcomeric organization. We identified mammalian diaphanous-related formin 1 (mDia1), a potent actin nucleation factor, as a binding partner of cytoplasmic Rb and found that mDia1 helps maintain the structural integrity of the sarcomere. These results reveal a novel non-nuclear function for Rb and suggest a potential mechanism of TNF-α-induced disruption of sarcomeric organization. DOI: http://dx.doi.org/10.7554/eLife.01228.001.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Keigo
authors.initials: K
authors.lastname: Araki
authors.forename: Keiko
authors.initials: K
authors.lastname: Kawauchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hirata
authors.forename: Mie
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
mesh_terms: D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012518:Sarcomeres; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016160:Retinoblastoma Protein; D014409:Tumor Necrosis Factor-alpha
keywords: CDK; phosphorylation; retinoblastoma protein; sarcomeric organization