Synthetic analogs of vitamin D for potential use in differentiation therapy should selectively regulate genes necessary for differentiation without inducing any perturbations in calcium homeostasis. PRI-1906, an analog of vitamin D2, and PRI-2191, an analog of vitamin D3 bind nuclear vitamin D receptor (nVDR) with substantially lower affinity than 1,25-dihydroxyvitamin D3 (1,25-D3), but have higher differentiation-inducing activity as estimated in HL-60 leukemia cell model. To examine how their increased differentiation-inducing activity is regulated we tested the hypothesis that membrane-mediated events, unrelated to nVDR, take part in the differentiation in response to PRI-1906 and PRI-2191. The induction of leukemia cell differentiation in response to the analogs of vitamin D was inhibited by LY294002 (phosphatidylinositol 3-kinase inhibitor), PD98059 (inhibitor of MEK1,2, an upstream regulator of extracellular-signal regulated kinase) and rapamycin (p70S6K inhibitor) pointing out that activation of signal transduction pathways unrelated to nVDR is necessary for differentiation. On the other hand, inhibition of cytosolic phospholipase A2 accelerated the differentiation of HL-60 cells induced by either 1,25-D3 or by the vitamin D analogs suggesting possible existence of a feedback loop between extracellular-signal regulated kinases and phospholipase A2.
Steroid hormones in plants and in animals are very important for physiological and developmental regulation. In animals steroid hormones are recognized by nuclear receptors, which transcriptionally regulate specific target genes following binding of the ligand. In addition, numerous rapid effects generated by steroids appear to be mediated by a mechanism not depending on the activation of nuclear receptors. Although the existence of separate membrane receptors was postulated many years ago and hundreds of reports supporting this hypothesis have been published, no animal membrane steroid receptor has been cloned to date. Meanwhile, a plant steroid receptor from Arabidopsis thaliana has been identified and cloned. It is a transmembrane protein which specifically recognizes plant steroids (brassinosteroids) at the cell surface and has a serine/threonine protein kinase activity. It seems that plants have no intracellular steroid receptors, since there are no genes homologous to the family of animal nuclear steroid receptors in the genome of A. thaliana. Since the reason of the rapid responses to steroid hormones in animal cells still remains obscure we show in this article two possible explanations of this phenomenon. Using 1,25-dihydroxyvitamin D3 as an example of animal steroid hormone, we review results of our and of other groups concordant with the hypothesis of membrane steroid receptors. We also review the results of experiments performed with ovarian hormones, that led their authors to the hypothesis explaining rapid steroid actions without distinct membrane steroid receptors. Finally, examples of polypeptide growth factor that similarly to steroids exhibit a dual mode of action, activating not only cell surface receptors, but also intracellular targets, are discussed.
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.