are involved in this process). therefore, a translocation of hormones, p53 and probably other hsp90 substrate proteins within cytoplasm is fast and tightly controlled. atp hydrolysis inside hsp90 nucleotide-binding pocket leads to the dissociation of the complex. next, steroid hormone receptors dimerize and are translocated to the nucleus (bottom, left). subsequently, shr-hormone complexes bind to particular dna sequences in the promoters of hormone-responsive genes to control their transcription. it should be stressed, that the movement of shrs inside the nucleus is also hsp90- and atp-dependent. but it is not known whether hsp90-hsp70-shr complexes can be transmitted through the nuclear envelope pores as a whole or could shuttle between separate hsp90 molecular complexes on both sides of the nuclear envelope the glucocorticoid receptor (gr) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with hsp90. in the absence of the steroid hormone cortisol, gr resides in the cytosol complexed with several chaperone proteins including hsp90 (see figure to the right). these chaperones maintain the gr in a state capable of binding hormone. a second role of hsp90 is to bind immunophilins (e.g., fkbp52) that attach the gr complex to the dynein protein trafficking pathway, which translocates the activated receptor from the cytoplasm into the nucleus. once in the nucleus, the gr dimerizes and binds to specific sequences of dna and thereby upregulates the expression of gr responsive genes. hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone, androgen, estrogen, and progesterone. cancerous cells cancerous cells overexpress a number of proteins, including growth factor receptors, such as egfr, or signal transduction proteins such as pi3k and akt (inhibition of these proteins may trigger apoptosis). hsp90 stabilizes various growth factor receptors and some signaling molecules including pi3k and akt proteins. hence inhibition of hsp90 downregulates the pi3k/akt pathway leading to downregulation of the anti-apoptotic protein bcl-w resulting in apoptosis of cancerous and senescent cells. interestingly, the disruption of hsp90 with nano-therapeutics has been implicated in targeting drug-induced resistance and relieves the suppression of natural killer (nk) immune cells in breast cancer. another important role of hsp90 in cancer is the stabilization of mutant proteins such as v-src, the fusion oncogene bcr/abl, and mutant forms of p53 that appear during cell transformation. it appears that hsp90 can act as a "protector" of less stable proteins produced by dna mutations. hsp90 is also required for induction of vascular endothelial growth factor (vegf) and nitric oxide synthase (nos). both are important for de novo angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues. it also promotes the invasion step of metastasis by assisting the matrix metalloproteinase mmp2. together with its co-chaperones, hsp90 modulates tumour cell apoptosis "mediated through effects on akt, tumor necrosis factor receptors (tnfr) and nuclear factor-κb (nf-κb) function.". also, hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis. clinical significance hsp90 plays apparently conflicting roles in the cell, as it is essential for both the creation and the maintenance as well as the destruction of proteins. its normal function is critical to maintaining the health of cells, whereas its dysregulation may contribute to carcinogenesis. the ability of this chaperone to both stabilize the 26s proteasome (which enables the cell to degrade unwanted and/or harmful proteins) and to stabilize kinases against the same proteasome demonstrates its functional diversity. the uses of hsp90 inhibitors in cancer treatment highlight hsp90's importance as a therapeutic target. targeting hsp90 with drugs has shown promising effects in clinical trials. for example, the hsp90 inhibitor geldanamycin has been used as an anti-tumor agent. the drug was originally thought to function as a kinase inhibitor but was subsequently shown to be an hsp90 inhibitor where it uses a compact conformation to insert itself into the atp binding site. hsp90 beta has been identified as one of the autoantigenic biomarkers and targets involved in human ovarian autoimmune disease leading to ovarian failure and thereby infertility. prediction and validation of the immunodominant epitope/s of hsp90 beta protein has been demonstrated using sera from infertile women having anti-hsp90 autoantibodies. the decapeptide ep6 (380-389)is a major immunogenic epitope of hsp90 followed by ep1 (1-12) and ep8 (488-498). knowledge of binding epitopes on the autoantigen is necessary to understand the subsequent pathologic events. predicted 3d structures of these peptides demonstrated that they exist in the loop conformation, which is the most mobile part of the protein. also, analysis of the sequences of hsp90 beta across several species reveals that ep6 peptide forms a part of a well-conserved motif. a polyclonal antibody generated to the immunodominant epitope- ep6 confirms similar biochemical and cellular immunoreactivity as seen with the patients' sera with anti-hsp90 autoantibodies. the study might generate new tools for the detection of disease-inducing epitopes and a possible therapeutic intervention. evolution sequence alignments of hsp90 have shown the protein to have about 40% sequence identity across all homologs, indicating that it is a highly conserved protein. there are two homologs, found in the cytosol and endoplasmic reticulum respectively. the presence of these two homologs was likely caused by a gene duplication event very early in the evolution of eukaryotes that may have accompanied the evolution of the endoplasmic reticulum or the nucleus. this inference is supported by the fact that the duplication is found in giardia lamblia, one of the earliest branching eukaryotic species. at least 2 other subsequent gene duplications occurred, which explains the different forms of hsp90 found in fungi and vertebrates. one divergence produced cognate and heat-induced forms of hsp90 in saccharomyces cerevisiae, while the second gene duplication event in the cytosolic branch produced the alpha and beta subfamilies of sequences that are found in all vertebrates. in a phylogenetic tree based on hsp90 sequences, it was found that plants and animals are more closely related to each other than to fungi. similar to the hsp90 protein, the gene for hsp70 protein also underwent duplication at a very early stage in the formation of eukaryotic cells and the homologs in the cytosol and endoplasmic reticulum resulted from this gene duplication event. these gene duplication events are important in terms of the origin of the eukaryotic cell and of the endoplasmic reticulum.