The down-regulation of c-myb oncogene expression has been associated with hematopoietic maturation. Indeed, recent evidence has demonstrated that the inappropriate expression of c-myb can block differentiation in some hematopoietic. In addition, it has been suggested that the down-regulation of c-myb MRNA expression may reflect a switch from constitutive expression to a cell cycle regulated mode o expression. The down-regulation of steady-state c-myb lmRNA levels during B-lymphoid maturation, as reflected in a tumor cell model, is regulated by a block to transcription elongation (attenuation) rather than at the level of transcription initiation. Recently, evidence has been presented that c-myb is expressed in several non-hematopoietic cell types including BALB/c3T3 cells where c-myb transcription appears to be cell-cycle regulated. The following proposed research will examine the expression of c-myb mRNA is relation to the cell cycle as a function of B and T lymphoid development and pursue its expression in BALB/c3T3 cells. These experiments will provide a context in which to examine the contribution of attenuation to the overall regulation of c-myb mRNA expression. Regulation of transcription by attenuation may provide a more rapid and sensitive mechanism to respond to external signals than initiation of transcription or the specific alteration of mRNA stability. To understand the mechanism of attenuation, a structural and functional analysis of the attenuator region will be initiated an directed towards the identification and assay of soluble factors which mediate a premature block to transcription elongation (or its relief). The possibility that such factors are modified and activated as a response to external stimuli is an attractive and testable hypothesis.
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