Steroid hormones regulate cellular processes by binding to intracellular receptors that, in turn, interact with discrete nucleotide sequences to alter gene expression. Because most steroid receptors in target cells are located in the cytoplasm, they need to get into the nucleus to alter gene expression. This process typically takes at least 30 to 60 minutes. In contrast, other regulatory actions of steroid hormones are manifested within seconds to a few minutes. These time periods are far too rapid to be due to changes at the genomic level and are therefore termed nongenomic or rapid actions, to distinguish them from the classical steroid hormone action of regulation of gene expression. The rapid effects of steroid hormones are manifold, ranging from activation of mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins). In some cases, these rapid actions of steroids are mediated through the classical steroid receptor that can also function as a ligand-activated transcription factor, whereas in other instances the evidence suggests that these rapid actions do not involve the classical steroid receptors. One candidate target for the nonclassical receptor-mediated effects are G protein-coupled receptors (GPCRs), which activate several signal transduction pathways. One characteristic of responses that are not mediated by the classical steroid receptors is insensitivity to steroid antagonists, which has contributed to the notion that a new class of steroid receptors may be responsible for part of the rapid action of steroids. Evidence suggests that the classical steroid receptors can be localized at the plasma membrane, where they may trigger a chain of reactions previously attributed only to growth factors. Identification of interaction domains on the classical steroid receptors involved in the rapid effects, and separation of this function from the genomic action of these receptors, should pave the way to a better understanding of the rapid action of steroid hormones.

Members of the Bag-1 family of cochaperones regulate diverse cellular processes including the action of steroid hormone receptors. The largest member of this family, Bag-1L, enhances the transactivation function of the androgen receptor. This occurs primarily through interaction with the NH 2 and COOH termini of the receptor. At the NH 2 terminus of the receptor, Bag-1L interacts with a region termed 5. Bag-1M, a naturally occurring variant of Bag-1L that binds to 5 but is defective in the COOH-terminal interaction, is less efficient in enhancing the transactivation function of the receptor. Surface plasmon resonance and transfection studies showed that the molecular chaperone Hsp70 contributes to the binding of Bag-1L to 5 and to the regulation of the transactivation function of the androgen receptor. Chromatin immunoprecipitation studies demonstrated that the androgen receptor, Hsp70, and Bag-1L are all targeted to the androgen response elements of the gene that encodes prostate-specific antigen. These studies demonstrate the regulation of transcriptional activity of androgen receptor by a molecular chaperone-cochaperone complex.

AGR2 enhances the invasion phenotype of prostate cancer cells while at the same time attenuating cell-cycle progression. This function, its expression pattern and the increased level of AGR transcripts in urine sediments of prostate cancer patients call for further exploration as a prostate cancer marker and a modulator of tumor growth and invasion.

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The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.