Meningiomas-true dependent tumors ?

isoforms, PR-A and PR-B. PR-B is 100 amino acids longer (NH2 terminus) than PR-A, but otherwise the two isoforms are identical. This finding is consistent between species, with the exception of rabbit, in which PR exists as a single form (5). Soon after the purification of PR, ER and AR were purified, although it was not until 1996 that second form of ER, ER-B, was discovered (6,7). Shortly after this milestone, the receptors for estrogen (1986), now known to be ER-A, progesterone (1987), and androgen (1988) were cloned. In humans, the ER-A gene resides on chromosome 6, where as ER-B is on chromosome 14. Human PR localizes to chromosome 11 and the AR gene resides on the X chromosome, underscoring its necessity for female, as well as male, development (6,8,9). Cloning of PR also allowed for the understanding of how the A and B isoforms are derived from the same gene. Interestingly, different species accomplish this feat via different methods, with the chicken isoforms arising as a result of different translation start sites within the same transcript, and the human isoforms occurring via different transcription start sites (5). In vitro experiments performed in the mid 1990s demonstrated that receptor binding to DNA is not hormone dependent. Experiments performed by the Pratt and Toft laboratories in the late 1980s demonstrated that the dissociation of HSPs from receptors is hormone-dependent (10,11). In the mid 1980s, steroid hormone receptors were shown to be phosphorylated in a hormone-dependent manner. Edwin Milgrom's laboratory showed that PR is phosphorylated, and with hormone administration, becomes hyperphosphorylated (5). These experiments suggested that steroid hormone receptor action is dependent on phosphorylation status. These discoveries were the culmination of the previous three decades of research and led to a well-supported model for steroid hormone receptor action: ligand binding induces a conformational change in the receptor, releasing heat shock protein-HSPs. The receptor undergoes hormone and DNA-dependent hyperphosphorylation, dimerizes, and binds its target DNA. The binding of the receptor to the SRE allows for the recruitment of general transcription factors and, subsequently, RNA polymerase to begin efficient transcription (5,12). Despite the great deal of information about steroid hormone action now known, many questions remain unanswered relating to receptor activation, regulation, and protein interactions. Since the early 1990s, it has been known that ligand-independent activation of PR and ER can occur. However, the full implications of these observations are not yet understood, although researchers have suggested that this type of activation may be associated with breast and uterine cancers. Yet another question deserving of further attention is how rapid cellular responses to steroid hormones, which cannot be explained by classic hormone transactivation, occur. This "nongenomic" mechanism was proposed as early as 1975 by Richard Pietras and Clara Szego to involve membrane-bound steroid receptor-induced increases in intracellular second messengers (13,14). Steroid hormones are involved in various aspects of growth, development, differentiation, reproduction, and homeostasis. They exert their effects by means of steroid hormone receptors, such as estrogen (ER), progesterone (PR), androgen (AR), glucocorticoid (GR), and mineralocorticoid receptors. Steroid hormone receptors belong to the steroid/thyroid hormone receptor superfamily, which includes thyroid hormone (TR), retinoic acid (RAR), and vitamin D3 receptors, as well as "orphan" receptors [e.g., ER-related-1 (ERR-1), ERR-2, and chicken ovalbumin upstream promoter-transcription factor], for which no ligands have yet been found. All members of the steroid and thyroid hormone receptor superfamily share similar structure consisting of modular domains from A to F (from NH2 to COOH terminus (15). Each receptor contains a unique A/B region, which is variable in length and sequence between the receptors. The A/B region allows for protein-protein interactions and transcriptional activation of target genes. The cysteine-rich C region is important for DNA binding and receptor dimerization. In some receptors, region D contains the Srðan MILENKOVIÆ I. BERISAVAC Dubravka CVETKOVIÆ-DO®IÆ I. BERISAVAC