Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

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During development cell types arise through the activation or repression of classes of specific genes. One hypothesis is that this phenomenon is realized by tissue-specific factors playing a role at the transcription level. Recently we have described a liver-specific nuclear protein, hepatocyte nuclear factor 1, that appears to be involved in the transcription of the fibrinogen and a1-antitrypsin genes. In this report we describe the purification of hepatocyte nuclear factor 1 and demonstrate that it interacts with essential promoter regions of many liver-specific genes, including albumin, a-fetoprotein, and transthyretin. This finding suggests that hepatocyte nuclear factor 1 could be one factor necessary for establishing the liver phenotype. We also show that this protein binds to the promoter of the surface-antigen gene of the hepatitis B virus, a virus characterized by a high degree of hepatotropism.Transcription in eukaryotes involves the specific interaction of nuclear proteins with discrete DNA elements located in the promoter or enhancer region ofgenes (1, 2). Promoter regions cover, generally, the 100-200 base pairs (bp) upstream of the cap site, whereas enhancers can be found at large distances in the 5' or 3' regions ofthe genes they regulate or even within them (1, 2). In general, the full transcription activity of a gene implies the interaction between its promoter and enhancer(s) components through the various proteins they bind.Some of the known DNA-binding proteins are restricted to a cell lineage (3-9). They interact with DNA sequences necessary for tissue-specific activation or repression ofgenes and constitute at least a part of the machinery eukaryotes use to synthesize proteins in a particular cell type. Transcriptional analysis of several hepatic genes (albumin, a-fetoprotein, and transthyretin) has revealed the presence of liverspecific promoters and/or enhancers (8-16). In several instances proteins binding to these regions have been described (8-10, 12, 17, 18). Analyzing the transcription of the fibrinogen genes we have localized in the 13chain promoter a functional sequence that binds a liver-specific nuclear protein, hepatocyte nuclear factor 1 (HNF1) (8). Because HNF1 also interacts with the gene for the a chain of fibrinogen and another liver-specific gene, a1-antitrypsin, we suggested that HNF1 could be involved in developmentally regulated gene expression in the liver (8) [a-32P]dATP (1 Ci = 37 GBq), 500 AM of bromodeoxyuridine, and 500 ILM of dCTP and dGTP. The full-length probe was purified on a 12% polyacrylamide gel, and 0.5 ng (50,000 cpm) were incubated with either 15 ,ug of a rat hepatoma cell line (Faza), liver nuclear extract, or 2 ,tg of heparin-Sepharose-purified liver extract for 45 min at room temperature. After 30 min of UV irradiation at room temperature with a Fotodyne UV transilluminator (A emission = 310 nm), the mixture was analyzed on an 8% sodium dodecyl sulfate (SDS)/polyacrylamide gel after reduction with 100 mM dithiothreitol. After fixation the ge...

The coordinate expression of genes during development and differentiation is thought to be accomplished by common transcription factors operating on the promoters of families of coexpressed genes. HNF-1 is a transcriptional factor involved in the expression of genes in the liver and was originally defined as playing a major role in coordinating the expression of the linked fibrinogen genes. We have isolated cDNA clones for HNF-1 using oligonucleotides prepared to the sequence of the purified protein. The sequence of HNF-1 shares the homeo domain, as well as short acidic and basic sequences with the POU family of transcriptional activators. Peptides from the protein interacting with the albumin proximal element, or B box (APF), and the factor interacting with the al-antitrypsin promoter (LF-BI) are found in the predicted sequence of HNF-1. HNF-1 mRNA is not present in the dedifferentiated hepatoma variant, C2, but reappears upon selection for gluconeogenesis coincident with the re-expression of liver-specific genes. Finally, the mRNA is not present in somatic cell hybrids in which liver-specific gene expression is extinguished. In contrast to earlier published results, we find that in addition to being present in the liver, HNF is expressed in the kidney, intestine, and spleen, but not in other tissues. This pattern of expression mirrors the complex pattern of expression of many genes, such as ~-fetoprotein, aa-antitrypsin, and fibrinogen, whose promoters contain HNF-1 sites. These data indicate that HNF-I is a more broadly acting transcription factor than has been indicated by previous work.