Myc family of genes; structure, expression, and activation in tumor pathogenesis

Doktorsritgerð í sameindalíffræði frá Karolinska Institutet, StokkhólmiThe aim of this study has been to identify the structural changes during c-myc activation in relation to tumor pathogenesis, to characterize the Bmyc gene, and to compare the structure and expression of myc gene family members. The myc family members are dispersed over the rat and mouse genome and are localized on different chromosomes. C-myc and Nmyc encode proteins that bind to different nuclear structures. Aberrant expression of c-myc is believed to contribute to the pathogenesis of many different tumors. Our studies on the rat immunocytoma have shown that chromosome translocations juxtapose c-myc and IgH-derived sequences in three B cell tumors in three different species. Juxtaposition of c-myc to an immunoglobulin locus and subsequent constitutive expression is regarded as an essential step in the genesis of mouse plasmacytoma, rat immunocytoma, and human Burkitt lymphoma. C-myc is regularly expressed in a wide variety of proliferating cells while Nmyc and Lmyc expression is limited to certain developmental stages and cell types. Bmyc has been isolated on the basis of the homology to c-myc second exon. Many tissues express Bmyc, independently of their developmental stage. During the embryonic development of the mouse and rat, c-myc, Nmyc, Lmyc and Bmyc are expressed in different regions, and the genes show different expression pattern in F9 embryonal carcinoma cells during growth stimulation, suggesting independent regulation. C-myc, Nmyc, and Lmyc are downregulated during differentiation of F9 cells to visceral endoderm, while Bmyc is constantly expressed at low level in all stages. Inhibitions of protein synthesis induces an elevation of c-myc, Lmyc, and Bmyc transcripts, suggesting that the genes are downregulated by a short-lived protein(s). Mitogenic stimulation with insulin and transferrin do not affect Nmyc, Lmyc, and Bmyc mRNA, while c-myc is upregulated. The rat Bmyc gene contains sequences related to the central part of c-myc, namely the first intron and the second exon, and the noncoding part of the the third exon. The homology drops in the 3' part of the c-myc second exon, but continues in the noncoding part of the third exon. The total predicted coding region of the Bmyc has been sequenced and a bacterial tryptophanE fusion protein has been made. The lack of coding sequences in Bmyc, corresponding the third exon of the c-myc, which is thought to be important for nuclear localization, DNA binding, transforming activity, and the putative protein destabilation signal, suggests that the Bmyc and c-myc gene products may have distinct activitis. Still, one of the two putative domains responsible for transformation activity of c-myc is found in the Bmyc sequence. These findings are discussed in the context of potential functional domains and the possibility of overlapping and distinct activities of myc-family proteins.Public Health Service grant number 3R01CA140554 awarded by the National Cancer Institute, Department of Health and Human Services; the Swedish Cancer Society; the Swedish Medical Research Concil; Hedlunds Stiftelse; the funds of Karolinska Institutet; the Concern Foundation, Los Angeles; Nordiska Forskarstipendier; The Swedish Institute; and Svenska Sällskapet för Medicinsk Forskin