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    • Hsp also called FK binding protein

    2022-11-14

    Hsp56 (also called FK506-binding protein 52, FKBP52) is one of the steroid receptor-associated immunophilins with tetratricopeptide repeat domains, which serve as binding sites for Hsp90 (Peattie et al., 1992). Hsp56 is elevated in breast cancer compared with normal breast tissue (Ward et al., 1999) and increased expression of the mRNA and protein by E2 through ER has been also reported (Kumar et al., 2001). The expression of Hsp110 was elevated in highly metastatic colorectal cells and was highly correlated with advancement of clinical stage and positive lymph node involvement (Hwang et al., 2003). Recently, the use of Hsp110 to form natural chaperone complexes with tumor protein 2-Methoxyestradiol receptor such as gp100 has been proposed as a powerful approach to therapeutic vaccine formulation with significant potential for clinical application (Wang et al., 2003). Similar to the function of Hsps, PDI related protein (also called endoplasmic reticulum protein 72, ERp72), an abundant luminal endoplasmic reticulum protein (Mazzarella et al., 1990), plays a role in the protein folding as a member of multiple molecular chaperone complex (Kuznetsov et al., 1997). PDI related protein has been reported to be controlled by E2 in largemouth bass (Bowman et al., 2002), but this is the first report, to our knowledge, that it can be stimulated by E2 in MCF-7 cells. Interestingly, it has been demonstrated that PDI (acting as a molecular chaperone to maintain properly folded proteins and regulating the redox state of proteins) cannot only alter ERα conformation, but also enhance the ERα-estrogen response elements’ interaction in MCF-7 cells (Schultz-Norton et al., 2006). Considering these data, in MCF-7 cells, PDI related protein regulated by E2 might serve as a molecular chaperone to regulate the E2 responsiveness. Recently, iterative PSI-BLAST searches identified an uncharacterized protein, XTP3-transactivated protein A, as a member of all-α nucleoside triphosphate pyrophosphatases superfamily performing ‘house-cleaning’ functions by hydrolyzing abnormal NTPs. (Moroz et al., 2005). The function of XTP3-transactivated protein A remains unknown, but in the response of E2, it might regulate the intracellular levels of abnormal NTPs in breast cancer cells. Using proteomics, stathmin 1 (oncoprotein 18, op18) was shown to be down-regulated in serum-free conditions, but its transcript was significantly up-regulated by E2 in MCF-7 cells with or without serum. Stathmin 1 is a conserved cytosolic phosphoprotein that regulates microtubule dynamics and has been reported to be overexpressed in human breast carcinomas (Curmi et al., 2000). The down-regulated protein level of stathmin 1 might be explained by the temporal regulation of stathmin 1 transcript; in cells cultured with or without serum, it was shown to be significantly down-regulated before being induced at 24h by E2. Aminoacylase 1 is a cytosolic, homodimeric, zinc-binding enzyme that catalyzes the hydrolytic deacylation of acylated L-amino acids and may function in their catabolism and salvage. In tumor tissue, the activity of cobalt-activated acylase was markedly increased in comparison with normal tissue, but no changes in aminoacylase 1 have been observed (Tyran et al., 1980). However, the expression of aminoacylase 1 was decreased in renal cell carcinoma (Balabanov et al., 2001) and in a group of small lung cancer cell lines and tumors (Cook et al., 1998), suggesting that the absence of aminoacylase 1 may result in the accumulation of acylated peptide growth factors responsible for cell transformation (Jones et al., 1991). In summary, in MCF-7 cells cultured with or without serum, the transcripts of 6 proteins (Hsp56, Hsp90α, Hsp110, protein PDI related protein, XTP3-transactivated protein A and stathmin 1) were significantly up-regulated and aminoacylase 1 transcript was significantly down-regulated by E2. The protein profiling and transcript expression patterns of E2-regulated proteins including Hsps in MCF-7 cells cultured with or without serum could elucidate the involvement of these proteins in breast carcinogenesis and enhance the understanding of changes induced by E2 on gene/protein expression regulation in E2-responsive cancer cells. These differentially expressed proteins (or transcripts) might be potent targets for treating patients with breast cancer. In addition, the differences between transcripts and their corresponding protein levels might be explained by the fact that post-transcriptional mechanisms may regulate expression of these molecules in breast cancer (Soufla et al., 2006), but further investigation is required.