Understanding cellular networks in the year 2001

In this issue, Müller-Tidow and colleagues (page 2091) identify the physical and functional interaction of the transcription factor B-myb with cyclin A1/cdk2, a complex that plays a critical role in regulating the cell cycle. B-myb is one of at least 3 members of the myb family of transcription factors, and like c-myb, it plays a role in hematopoietic cell proliferation. Many aspects of the overlapping and distinct functions of these transcription factors remain to be identified, but in this report phosphorylation of B-myb by the cyclin A1/cdk2 complex is shown to enhance the ability of B-myb to activate gene expression, and in particular, the human cyclin A1 gene promoter. Similar but distinct regulatory proteins can exert specific functions within the cell if their activity is variably regulated in response to changes in the cell cycle or in response to external stimuli. The cyclin A1/cdk2 complex is present only during S phase, thus B-myb should maximally activate gene expression at S phase, when the cyclin A/cdk2 complex is most abundant.

Currently, microarray technologies and subtraction libraries are commonly used to identify the target genes of transcription factors, to characterize the cellular response to cytokines, or to differentiate one cell type from another. This study points out at least one of the limitations of these approaches, namely, their inability to detect posttranslational modifications of proteins, which may be very important in understanding cell cycle–dependent events. Cell cycle–dependent regulation of gene expression is perhaps best typified by the regulation of E2F function, a transcription factor essential for DNA synthesis. E2F is activated by the cyclin/cdk dependent phosphorylation of its binding partner, the retinoblastoma gene product (Rb), which releases E2F, allowing it to activate gene expression. Critical posttranslational regulation of function is not identified by measuring RNA levels or even the amount of protein present in the cell. Sophisticated and careful approaches will be certainly required to delineate the precise role of B-myb in hematopoietic development.