James E. Darnell, Jr. M.D.
Vincent Astor Professor
Differentiation, development and homeostasis in adult tissues depend on the
execution of a correct transcriptional program in particular cells. In
turn, many of the signals which cells receive and interpret to execute such
programs come in large part from polypeptides that bind to the cell surface.
These signalling polypeptides are active both in development and
particularly in adults to maintain correct hemopoeisis condtions and to
respond to outside stresses such as infections.
Our laboratory group studies how signals from the cell surface do, in
fact, affect nuclear transcription. These studies originally used as a
interferon stimulation of transcription of a limited set of genes.
The interferons specifically call forth the transcription of a
limited set of otherwise quiescent genes, and we have at least partly
unraveled the mechanism of this stimulation. Latent cytoplasmic proteins
termed STATs (for Signal Transducers and Activators of Transcription) become
active as DNA-binding factors only after interferon occupies its receptor.
We obtained molecular clones for the STAT proteins, and antisera to these
proteins allowed the demonstration that interferon-dependent tyrosine
phosphorylation followed by dimerization of the proteins and nuclear
translocation is the basis for gene activation. We extended this pathway to
include many ligands other than the interferons, discovered several other
mammalian STATs as well as a Drosophila STAT that functions in early
development. Over 40 polypeptide ligands are now known to activate one of
the seven know STATs in mammals. Thus the pathway appears to serve a very
general role in cell regulation. Among the important newer findings on the
biologic front is the realization that some STATs are constitutively
activated in cancer cells. The basis for the role of genes activated
constitutively by STATs is under study. In addition the
crystallographic structure has been determined together with
group and we are intensely studying the functional domains of STAT proteins
biochemically and structurally. Finally, the proteins responsible for steps
in the activation-inactivation cycle are becoming known and this is also
Research group classification: Molecular, Cell and Developmental Biology
Key words: transcriptional control/cytokines/signal transduction/STAT proteins