(B) Cytoplasmic translocation of Rb is caused by TNF- treatment. calves, are one of three main muscle groups in the body, and a range of chronic diseasesincluding cancer, heart disease and AIDScan cause wasting and a loss of strength in these muscles. Many different cellular processes are known to be involved in the degeneration of skeletal muscle during illness. For example, in people suffering from cancer, the immune response produces large numbers of molecules called inflammatory cytokines to combat the cancer cells, and these molecules are thought to have a role in the breakdown of skeletal muscle. A cytokine called tumour necrosis factor alpha, or TNF- for short, is thought to cause muscle damage, but the details of this process are not fully understood. One possibility is that TNF- interacts with a protein called Rbshort for retinoblastoma proteinthat suppresses the proliferation of cells that leads to cancer. However, if TSPAN32 this protein is modified by a chemical process called phosphorylation, the Rb molecules will not be able to suppress the genes that lead to excessive cell growth. The hyperphosphorylation of Rb has been observed in many cancer cells, and it has been shown that high levels of TNF- in cells results in Rb not working properly, but it has not been clear if faulty Rb also leads to the breakdown of skeletal muscle. Now Araki et al. provide evidence that the phosphorylation of Rb by TNF- leads to skeletal muscle degeneration. Araki et al. found that in muscle cells that contain high concentrations of TNF-, the Rb molecules move from the nuclei of the cells, where they interact with genes, to the cytoplasm, where they disrupt the formation of structural fibres. This means that Rb inhibits the ability of muscle cells to slide over one during contractions and relaxation, as happens in normal muscle tissue. If confirmed by further experiments, these results could lead to the development of new approaches for the treatment of skeletal muscle degeneration. DOI:http://dx.doi.org/10.7554/eLife.01228.002 == Introduction == 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). The underlying intercellular mechanism is currently thought to be multifactorial. Inflammatory cytokines, particularly TNF-, have been shown to be key mediators of cancer-related skeletal muscle degeneration (Tisdale, 2002;Seruga et al., 2008). Elevated levels of TNF- precede the onset of cancer-related skeletal muscle degeneration and act through several cancer-related signaling pathways such as the p53 and nuclear factor kappa B (NF-B) pathways (Guttridge et al., 2000;Cai et al., 2004;Schwarzkopf et al., 2006). Retinoblastoma protein (Rb) prevents tumor formation by inducing differentiation, controlling cell-cycle progression, and maintaining genomic stability (Burkhart and Sage, 2008). To date, numerous studies of Rb function have focused on the transcriptional regulation of E2F. Rb forms a transcriptional repressor complex with two protein groups, E2F transcription factors and LXCXE motif-containing proteins (Halaban, 2005;Burkhart and Sage, 2008). Rb p38-α MAPK-IN-1 activity is regulated by sequential phosphorylation on several serine and threonine residues, first by cyclin D/cyclin-dependent kinase 4 (CDK4) and then by cyclin E/CDK2 complexes (Halaban, 2005). This serial phosphorylation p38-α MAPK-IN-1 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). Consequently, selective CDK inhibition is considered a potentially useful approach for cancer treatment (Malumbres and Barbacid, 2009). In addition, inactivation of Rb, which is induced by TNF- treatment, has been shown to lead to various cellular behaviors including proliferation of vascular smooth muscle cells (Rastogi et p38-α MAPK-IN-1 al., 2012) and apoptosis of fibroblasts and aortic endothelial cells (Chau and.