Chaperones and Signaling by Nuclear Hormone Receptors

Similar to their function in feedback control of the heat shock response by chaperoning HSF1, Hsp70, Hsp90, and its co-chaperones are also involved in chaperoning and regulating nuclear hormone receptors. Association of the heat shock protein hsp90 with steroid hormone receptor products was described two decades ago (Catelli et al. 1985; Sanchez et al. 1985). Since then, a complex scenario of different steps in hormone receptor maturation, activation, and deactivation by chaperones has emerged (see the chapter by W.B. Pratt et al., this volume). Maturation of hormone receptor starts with binding of Hsp70 and Hsp40 to the nascent aporeceptor at the ribosome and the subsequent transfer to Hsp90 through the adapter protein Hop (Kosano et al.

1998). Replacement of Hop by p23 and binding of immunophilins then leads to the complete aporeceptor complex containing a dimer of Hsp90 (Young and Hartl 2002). Upon hormone binding, the aporeceptor complex falls apart and the hormone-bound DNA-binding and transactivating receptor is released and translocated to the respective hormone response elements at the DNA. PPIase activity of interacting immunophilins such as FKBP51 contributes to transac-tivation properties of the protein-hormone complex (Riggs et al. 2003). This demonstrates a role of prolyl- cis-tr ans-isomerization in associated proteins for transactivation. In addition, the PPIase domain of receptor complexbound immunophilins and immunophilin-like tetratricopeptide repeat domain proteins such as protein phosphatase 5 (Silverstein et al. 1997) can specifically interact with the cytoplasmic transport protein dynein, which could be responsible for retrograde transport of the receptor complex to the nuclear pore (Pratt et al. 2004).

Since the physiologically relevant hormone response in most cases should be transient, downregulation often proceeds within minutes and involves p23 and Hsp90 action. The binding of p23 and Hsp90 to the DNA-bound hormone receptor leads to disassembly of hormone receptor complex and release from DNA (Freeman et al. 2000). In addition, a transcriptional repressing activity in cis at the hormone responsive and other promoters could be measured for p23 (Freeman and Yamamoto 2002; Morimoto 2002), suggesting that this co-chaperone could be involved in transcription factor complexes and broadly contribute to transcriptional regulation under certain conditions.

An isoform of the protein BAG-1 (Bcl2-associated anhanogene-1; Takayama et al. 1995), BAG-1M, was initially identified as a glucocorticoid receptor (GR) binding protein, which translocates to the nucleus and preferentially interacts with the activated receptor (Zeiner and Gehring 1995; Zeiner et al.

1999). It turned out that BAG-1 is a ADP-exchange factor for Hsp70 and Hsc70 that probably acts similarly to the GrpE-protein for DnaK, the prokary-otic homolog of Hsp70 (Hohfeld and Jentsch 1997; Takayama et al. 1997). Interestingly, Hsp70 together with the BAG-1M or a shorter isoform, BAG-1L, also contribute to hormone receptor regulation: BAG-1M,L interact with the hinge region of the GR and inhibit dexamethasone-induced receptor-mediated transcription (Schneikert et al. 1999). Possibly, BAG-1-Hsp70 complexes are involved in downregulation of the activated GR (Nollen and Mo-rimoto 2002). In contrast, BAG-1L, probably together with Hsp/Hsc70, interacts with the androgen receptor and vitamin D3 receptor and stimulates transcriptional activation of respective genes (Froesch et al. 1998; Guzey et al. 2000).

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