The myb gene family in cell growth, differentiation and apoptosis

Abstract

The myb gene family consists of three members, named A, B and c-myb which encode nuclear proteins that function as transcriptional transactivators. Proteins encoded by these three genes exhibit a tripartate structure with an N-terminal DNA-binding domain, a central transactivation domain and a C-terminal regulatory domain. These proteins exhibit highest homology in their DNA binding domains and appear to bind DNA with overlapping sequence speci®cities. Transactivation by myb gene family varies considerably depending on cell type and promoter context suggesting a dependence on interaction with other cell type speci®c co-factors. While the C-terminal domains of A-Myb and c-Myb proteins exert a negative regulatory eect on their transcriptional transactivation function, the C-terminal domain of BMyb appears to function as a positive regulator of this activity. One or more of these proteins interact with other transcription factors such as Ets-2, CEBP and NF-M. In addition, expression of these genes is cell cycleregulated and inhibition of their expression with antisense oligonucleotides has been found to aect cell cycleprogression, cell division and/or dierentiation. Members of the myb gene family exhibit dierent temporal and spatial expression patterns suggesting a distinctive function for each of these genes. Gene knockout experiments show that these genes play an essential role in development. Loss of c-myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis. A-myb null mutant mice, on the other hand are viable but exhibit growth abnormalities, and defects in spermatogenesis and female breast development. While the role of c-myb in oncogenesis is well established, future experiments are likely to provide further clues regarding the role of A-myb and B-myb in tumorigenesis.

The carbonic anhydrase I locus contains a c-Myb target promoter and modulates differentiation of murine erythroleukemia cells

“…The Myb proto-oncogene was first identified as the cellular homolog of two replication-defective acute transforming avian retroviruses, AMV and E26, that cause myeloblastic and erythroblastic leukemias (Radke et al, 1982;Oh and Reddy, 1999). Expression of c-Myb is predominantly associated with immature hematopoietic cells.…”

“…Three distinct functional domains have been identified on c-Myb: a DNA-binding domain (DBD), a transactivation domain (TA) and a negative regulatory domain (NRD) (Oh and Reddy, 1999). The c-Myb DBD is located at the amino-terminus and is a highly conserved region consisting of three tandem repeats of approximately 50 amino acids each (R1, R2 and R3).…”

“…Studies of potential c-Myb target promoters have demonstrated that c-Myb activity can be modulated by interaction with other transcription factors and coactivators as well as post-translational modifications (Oh and Reddy, 1999). For example, c-Myb activates mim-1, GBX-2 and tom-1 by cooperating with members of the C/EBP transcription factor family (Ness et al, 1993;Burk et al, 1997), which are highly expressed in myelomonocytic cells.…”

Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk

“…This data imply that a large fraction of the human population is carrier of B-MYB alleles that might be associated with a reduced risk of developing neoplastic disease. Oncogene (2008Oncogene ( ) 27, 2929Oncogene ( -2933doi:10.1038/sj.onc.1210947;published online 19 November 2007 Keywords: transcription; neuroblastoma; colon cancer; leukaemia; apoptosis B-MYB is a putative proto-oncogene required for mammalian development and involved in cell proliferation and survival (Oh and Reddy, 1999;Tanaka et al, 1999;Sala, 2005). Although there is still no evidence of its direct involvement in human cancer, several studies have revealed that B-MYB is either amplified or overexpressed in different human malignancies, while its expression in neuroblastoma patients correlates with poor survival (Raschella et al, 1999;Forozan et al, 2000;Tanner et al, 2000;Bar-Shira et al, 2002).…”

“…Aberrant B-MYB expression might promote cancer development through increased activity of downstream target genes. B-MYB target genes have been found that promote cell cycle progression or resistance to apoptosis, although B-MYB effects might also occur through other mechanisms (Oh and Reddy, 1999;Sala, 2005). While the above described studies support the hypothesis that B-MYB is a proto-oncogene, a recent report shows that an inactivating mutation of B-MYB in zebrafish actually promotes chemical carcinogenesis as a consequence of genomic destabilization (Shepard et al, 2005).…”