The proliferation of animal cells is tightly regulated by polypeptide growth factors, which interact with their specific cell surface receptors and trigger a series of biochemical events that culminate in the rapid activation of a set of genes without requiring de novo protein synthesis. Among these """"""""immediate-early"""""""" genes activated by growth factors are those that encode transcription regulators, including members of the Fos and Jun families, Myc, Rel and several proteins containing zinc fingers or helix-loop-helix motifs. These growth factor-induced transcription regulators are likely to activate other genes expressed later in the genetic program for growth. Like the proto-oncogenes fos and jun, some of the immediate-early genes are also activated by other extracellular signals that cause disparate biological effects, suggesting that their encoded transcription factors may function as nuclear third messengers that serve to interpret diverse environmental changes into long-term cellular responses. One such immediate-early transcription regulator is Nur77, which is the only member of the steroid/thyroid hormone receptor superfamily known to date to be rapidly and transiently activated by extracellular signals. In this proposal, experiments are designed to elucidate the biochemical activities and biological roles of Nur77. First, the proposal aims to dissect the structure-function relationships of the Nur77 protein: to identify the functional domains responsible for transactivation, nuclear localization, and possible interaction with other regulatory proteins. Second, the effects of phosphorylation on the activities of Nur77 will be examined, as Nur77 is differentially phosphorylated when synthesized upon stimulation by various agents. Third, the target genes activated by Nur77 under various conditions of stimulation will be identified and compared. Finally, the pattern of nur77 expression during growth and development will be described, and correlated with developmental regulation of the activities of Nur77 as a transcription factor as examined in transgenic mice. These studies may lead to a better understanding not only of how Nur77 might mediate the effects of mitogenic growth factors and participate in cell growth control, but how it might mediate cellular responses to other environmental stimuli as well.
| Yazdanbakhsh, K; Choi, J W; Li, Y et al. (1995) Cyclosporin A blocks apoptosis by inhibiting the DNA binding activity of the transcription factor Nur77. Proc Natl Acad Sci U S A 92:437-41 |
| Davis, I J; Lau, L F (1994) Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol Cell Biol 14:3469-83 |
| Davis, I J; Hazel, T G; Chen, R H et al. (1993) Functional domains and phosphorylation of the orphan receptor Nur77. Mol Endocrinol 7:953-64 |
