PHARMACOLOGIC AND MOLECULAR CONTROL OF C-JUN IN LEUKEMIA
Principal Investigator: MATTHEW SHERMAN
Abstract: The early response proto-oncogene c-jun has been implicated in cell growth and differentiation. The c-jun-encoded product is structurally and functionally similar to a component of the transcription factor AP-1. Jun/AP-1 binds to DNA sequences that regulate transcription of genes responsive to phorbol esters and growth factors. Previous work has demonstrated that HL-60 promyelocytic leukemia cells differentiate into monocyte-like cells following exposure to pharmacologic agents including phorbol esters and tumor necrosis factor (TNF). This induction of monocytic differentiation is associated with changes in expression of a variety of genes. For example, in contrast to the down-regulation of c-- myc RNA levels, monocytic differentiation is associated with increases in c-sis, c-fos, and TNF transcripts. Furthermore, HL-60 cells induced along the monocytic lineage express both the macrophage-specific colony stimulating factor (M-CSF), and the M-CSF receptor (c-fms) genes. The 5' flanking promotor region of the c-myc, TNF and M-CSF genes contain several elements with sequence homology to a Jun/AP-1 site which may be involved in the regulation of gene transcription. Preliminary results demonstrate that expression of c-jun is increased through activation of protein kinase C by phorbol esters such as 12-0-tetradecanoylphorbol-1.3- acetate (TPA). Moreover, treatment of HL-60 cells with TNF is also associated with an increase in c-jun transcripts. These results thus provide the basis for exploring the transcriptional regulation of c-jun during monocytic differentiation of human myeloid leukemia cells. Furthermore, the molecular mechanisms involved in the posttranscriptional regulation of c-jun gene expression will be studied. The cis-regulatory DNA elements and trans-acting proteins that control c-jun expression in myeloid cells will be identified. Thus, it is hoped that these studies will provide certain insights into the regulation of early response gene expression and possibly lead to the design of novel approaches to overcome the block in the differentiation of leukemia cells.
Funding Period: 1991-07-01 - 1992-10-31
more information: NIH RePORT