My laboratory has a longstanding interest in the cellular and molecular actions of steroids, especially glucocorticoids and oxysterols. New interests include estrogens and endocrine disruptors. . Endocrine disruptors are compounds found in nature or as byproducts of manufacturing processes that interact with steroid receptors- especially estrogen receptors- to interfere with their normal functions.

Glucocorticoid actions on leukemic cells:

Glucocorticoids cause many types of malignant lymphoid cells to die by the process known as apoptosis. Using a human leukemic cell line, we have discovered that the mechanism of this process involves rapid regulation of c-myc, c-jun, ODC and other genes important for cell cycling. Gene array analyses are being used in combination with somatic cell genetics to identify these. Interactions of the PKA, PKC and glucocorticoid pathways are being explored.

Structural studies of steroid receptors:

The functional structure of the N-terminal transcription-activating domain of several receptors is under study, using recombinant peptides and proteins and solution biophysical methods. This domain seems to lack tertiary structure in its native state, but structure can be induced by use of osmolytes or by binding the domain to certain partner proteins. Endocrine disruptors may affect the structure and functions of this domain.

Use of glucocorticoid receptor gene fragment to cause cell death in the absence of steroid:

We have discovered that certain very small fragments of a mutated form of the glucocorticoid receptor are capable of causing cell death when transfected into several kinds of cancer cells. The mechanism of this effect may involve interaction with cellular transcription machinery. These molecular steps are being worked out, and the application of this finding for a potentially novel form of therapy is being pursued through studies on efficient delivery mechanisms.