Molecular Endocrinology, Vol 7, 104-113, Copyright © 1993 by Endocrine Society

ARTICLES

Synergistic induction of apoptosis with glucocorticoids and 3',5'- cyclic adenosine monophosphate reveals agonist activity by RU 486

DJ Gruol and J Altschmied
Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037-1099.

Glucocorticoids induce a programmed cell death in immature murine T cells through a process that has been named apoptosis. Cyclic AMP- dependent protein kinase (PKA) activity contributes to this response but acts through an undefined mechanism. Steroid-induced cytolysis can be completely blocked by the glucocorticoid antagonist RU 486, which inhibits the transformation of the glucocorticoid receptor (GR) into a fully activated transcription factor. However, the ability of cAMP to act synergistically with steroids to cause apoptosis has revealed that a limited portion of RU 486-bound GR can translocate to the nucleus and contribute to a loss of cell viability. The combination of cAMP and RU 486 was also found to act cooperatively to regulate mRNA levels of specific genes. A 5-kilobase VL30 retroviral element transcript, which had previously been shown to be regulated synergistically by cAMP and dexamethasone, was strongly induced by the combination of RU 486 and cAMP. There was no agonist effect of RU 486 on the induction of the VL30 5-kilobase transcript in a variant cell line with defective PKA. Thus, the ability of RU 486 to act as an agonist, in this instance, was cAMP dependent. A similar response was also seen with the chondroitin sulfate proteoglycan core protein gene. On the other hand, mouse mammary tumor virus mRNA levels, which were not affected by cAMP alone, did not respond to a combination of RU 486 and cAMP. Studies of GR function, evaluating nuclear translocation and DNA binding at a GR- specific DNA regulatory element site found no evidence for a general effect of PKA activation on these receptor functions. We propose that cAMP may contribute to the induction of apoptosis at a step beyond receptor transformation by promoting an interaction between GR and other gene-specific regulatory proteins. Moreover, this interaction is sufficient to overcome the inhibition imposed by RU 486 on the functional capacity of nuclear glucocorticoid receptors.

This article has been cited by other articles:

				J. A. Meyers, J. Taverna, J. Chaves, A. Makkinje, and A. Lerner Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells Clin. Cancer Res., August 15, 2007; 13(16): 4920 - 4927. [Abstract] [Full Text] [PDF]

				E. Roggero, A. R Perez, M. Tamae-Kakazu, I. Piazzon, I. Nepomnaschy, H. O Besedovsky, O. A Bottasso, and A. del Rey Endogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection. J. Endocrinol., August 1, 2006; 190(2): 495 - 503. [Abstract] [Full Text] [PDF]

				R. Sasson, K. Tajima, and A. Amsterdam Glucocorticoids Protect against Apoptosis Induced by Serum Deprivation, Cyclic Adenosine 3',5'-Monophosphate and p53 Activation in Immortalized Human Granulosa Cells: Involvement of Bcl-2 Endocrinology, February 1, 2001; 142(2): 802 - 811. [Abstract] [Full Text] [PDF]

				V. Doucas, Y. Shi, S. Miyamoto, A. West, I. Verma, and R. M. Evans Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor PNAS, October 4, 2000; (2000) 220413297. [Abstract] [Full Text]

				J. Schmidt, R. Gold, L. Schonrock, U. K. Zettl, H.-P. Hartung, and K. V. Toyka T-cell apoptosis in situ in experimental autoimmune encephalomyelitis following methylprednisolone pulse therapy Brain, July 1, 2000; 123(7): 1431 - 1441. [Abstract] [Full Text] [PDF]

				H.-S. Wang, H. J. Cao, V. D. Winn, L. J. Rezanka, Y. Frobert, C. H. Evans, D. Sciaky, D. A. Young, and T. J. Smith Leukoregulin Induction of Prostaglandin-Endoperoxide H Synthase-2 in Human Orbital Fibroblasts. AN IN VITRO MODEL FOR CONNECTIVE TISSUE INFLAMMATION J. Biol. Chem., September 13, 1996; 271(37): 22718 - 22728. [Abstract] [Full Text] [PDF]

				V. Doucas, Y. Shi, S. Miyamoto, A. West, I. Verma, and R. M. Evans Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor PNAS, October 24, 2000; 97(22): 11893 - 11898. [Abstract] [Full Text] [PDF]