Lipid rafts have been known to be platforms to initiate cellular signal transduction of insulin-like growth factor (IGF) inducing skeletal muscle differentiation and hypertrophy. Here, tripartite motif 72 (TRIM72), with a really interesting new gene (RING)-finger domain, a B-box, two coiled-coil domains, and a SPRY (SPla and RYanodine receptor) domain, was revealed to be predominantly expressed in the sarcolemma lipid rafts of skeletal and cardiac muscles. Adenoviral TRIM72 overexpression prevented but RNAi-mediated TRIM72 silencing enhanced C2C12 myogenesis by modulating the IGF-induced insulin receptor substrate-1 (IRS-1) activation through the molecular association of TRIM72 with IRS-1. Furthermore, myogenic activity was highly enhanced with increased IGF-induced Akt activation in the satellite cells of TRIM72 À/À mice, compared to those of TRIM72 þ / þ mice. Because TRIM72 promoter analysis shows that two proximal E-boxes in TRIM72 promoter were essential for MyoD-and Akt-dependent TRIM72 transcription, we can conclude that TRIM72 is a novel antagonist of IRS-1, and is essential as a negative regulator of IGF-induced muscle differentiation.

A micronucleus test was performed on 75 subjects of whom 38 presented with cancer of the upper digestive tract and 37 were free of disease; the absence of cancerous or pre-cancerous lesions in this latter group was confirmed by endoscopy and vital staining. The daily levels of alcohol and tobacco consumption of the 75 subjects were determined by precise questioning: 78% of the non-cancerous subjects smoked less than 10 g of tobacco per day whereas 79% of the cancer patients smoked 10 g or more daily. The alcohol intake of 78% of the non-cancerous subjects and 63% of the cancer patients was less than 101 ml per day. Only 10% of the cancer patients had combined daily intake levels corresponding to the threshold of sensitivity of the micronucleus test as defined by previous studies. The mean frequency of micronucleated buccal cells was 0.26% in the cancer patients and 0.13% in the non-cancerous subjects. All non-cancerous patients presented a negative test. Only 5% of the cancer patients presented a micronucleated cell frequency above 1% and could thus be considered as positive. It thus appears that the micronucleus test was not significantly positive in our population of 38 cancer patients.

A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.