CONTROL OF TGF-BETA RECEPTOR EXPRESSION IN BONE

Michael Centrella, Changhua Ji, Thomas L. McCarthy

Department of Surgery, Plastic Surgery Section, Yale University School of Medicine, 333 Cedar Street, PO Box 208041, New Haven, CT 06520-8041,

Received 12/1/97 Accepted 12/5/97

10. NUCLEAR FACTOR CBFa

The CBFa transcription factors were independently identified by several labs and termed CBFs, PEBP2 alphas, AMLs, or NMPs. Due to confusion with names of diseases or other transcription factor families, it has been suggested that the two subunits for these factors should be termed as CBFa and CBFb. Thus, active nuclear factor contains one CBFa subunit (CBFa1, CBFa2 or CBFa3), and a common CBFb subunit that greatly increases CBFa subunit binding to DNA (99-102). CBFa subunits contain a so-called Runt homology domain, derived from its similarity to a transcription factor involved in cell fate associated with body segmentation, sex determination, and neurogenesis in Drosophila. The CBFa Runt domain contains binding sites for DNA and for the CBFb subunit. The COOH-terminal region of the CBFa subunit contains a transactivation domain required for CBFa dependent gene transcription. CBFa1 and CBFa2 also contain sites that can be phosphorylated by components of the mitogen activated protein (MAP) kinase system that are activated in response to certain growth factors and cytokines, and perhaps phorbol esters. Phosphorylation may have a potent stimulatory effect on CBFa dependent gene transcription (103,104). CBFb subunits tend to be ubiquitous and over expressed, and uncomplexed CBFb subunits accumulate in the cytoplasm (99). Gene expression regulated by CBFa can therefore result from: 1) variations in three different CBFa subunits that themselves may distinguish several cis-acting DNA binding sequences in subtle ways; 2) by the amount or the intracellular location of the common CBFb subunit; 3) or by growth regulators that activate or suppress osteogenic cell function.

In addition, other proteins can associate with the CBFa or CBFb subunits independently. For example, transcription factors termed C/EBPs physically interact with CBFa2 through the Runt domain common to all CBFa subunits, and synergistically enhance M-CSF receptor (c-fms) gene expression in macrophage-like cells (105). Other interactions have also been noted with nuclear factors c-Myb and with Ets family members in the neutrophil elastase and myeloperoxidase promoters (106,107). Functional levels of C/EBP beta and C/EBP delta are found in osteoblasts (108) predicting that similar interactions may occur in bone cells. CBFb subunits have wider tissue distribution than CBFa subunits. This and the existence of a large CBFb cytoplasmic pool, suggests that other binding partners exist, or modifications are needed to promote nuclear localization or association with CBFa subunits, but how this occurs is not yet clear (100, and personal communications from Dr. Yoshiaki Ito, Kyoto University, Japan; and Dr. J. Peter Gergen, State University of New York at Stonybrook).