Studio dell'interazione tra c-MYC ed i complessi iston-metil-trasferasici

The c-Myc transcription factor
The human c-myc gene was first identified as a homolog of the v-myc oncogene found in a specific subgroup of avian retrovirus, which induces myeloid leukemia, sarcomas, liver, kidney, and other tumors in chickens (Vennstrom et al., 1982). c-myc is located on human chromosome 8q24, and consists of three exons. Its transcription may be initiated at one of three promoters and translation at the AUG start site in the second exon produces a major 439-amino-acid, 64 kDa c-Myc protein (Dalla Favera et al., 1982). Myc has generally been associated with the promotion of cellular growth and proliferation, desensitization to growth-inhibitory stimuli, blockade of cell differentiation, cellular immortalization, and oncogenic transformation, as well as sensitization to apoptosisinducing signals. Activation of the c-myc proto-oncogene contributes to progression of a wide range of neoplasias. The c-Myc protein or the cmyc gene is over-expressed in a variety of human cancers, namely 80% of breast cancers, 70% of colon cancers, 90% of gynecological cancers, 50% of hepatocellular carcinomas and a number of hematological tumors, the better known being Burkitt Lymphoma where the c-myc gene is translocated to the loci of immunoglobulin genes (heavy chain, kappa, or lambda light chain loci) leading to inappropriate overexpression of the oncogene (Kufe, 2003). The c-Myc protein is a short-lived transcription factor of the basic helix-loop-helix leucine zipper (bHLH-LZ) family that is involved in the control of proliferation, cell differentiation, and apoptosis. Monomeric c-Myc has no ability to bind DNA either in vitro or in vivo, (Littlewood et al., 1992) and requires heterodimerization with Max through its bHLH-LZ domain to specifically recognize its target sites (Amati et al., 1993; Littlewood et al., 1992). Max is present in stoichiometric excess to Myc, and can also form homodimers or heterodimers with several related proteins, known as Mad1, Mad2, Mad3, Mad4 and Mnt (Grandori et al., 2000; Hurlin et al., 1997; Hurlin et al., 1994; Hurlin et al., 1995). The dimers all bind directly to the same consensus DNA sequence CACGTG (canonical E-box), although other “non-canonical E-boxes” can be alternatively recognized by Myc-Max dimers (Grandori et al., 1996). In vivo, MycMax complexes are predominant in proliferating cells and in cells reentering the cell cycle, whereas Mad-Max complexes are predominant in resting or differentiated cells (Adhikary and Eilers, 2005; Frank et al., 2001).