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.
Highlights
Skeletal muscle degeneration, which is characterized by the progressive depletion of muscle strength, occurs in a variety of chronic diseases including advanced cancer, congestive heart failure, and AIDS (Tisdale, 2002)
When cyclin-dependent kinase 4 (CDK4) was depleted by short hairpin RNA, cytoplasmic accumulation of retinoblastoma protein (Rb) induced by TNF-α was decreased (Figure 1F–H)
These results suggest that phosphorylation of Rb by CDK4 triggers its cytoplasmic translocation in human skeletal muscle myotubes (HSMMs)
Summary
Skeletal muscle degeneration, which is characterized by the progressive depletion of muscle strength, occurs in a variety of chronic diseases including advanced cancer, congestive heart failure, and AIDS (Tisdale, 2002). Rb activity is regulated by sequential phosphorylation on several serine and threonine residues, first by cyclin D/cyclin-dependent kinase 4 (CDK4) and by cyclin E/CDK2 complexes (Halaban, 2005). This serial phosphorylation of Rb induces dissociation of the transcriptional repressor complex, allowing expression of E2F-target genes, which are required for many cellular processes. Loss of Rb function in many cancer cells is frequently caused by aberrant CDK-mediated phosphorylation (Chau and Wang, 2003; Burkhart and Sage, 2008). Selective CDK inhibition is considered a potentially useful approach for cancer treatment
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