Abstract
FK506 binding protein 51 (FKBP51) is an immunophilin physiologically expressed in lymphocytes. Very recently, aberrant expression of this protein was found in melanoma; FKBP51 expression correlates with melanoma aggressiveness and is maximal in metastatic lesions. FKBP51 promotes NF-κB activation and is involved in the resistance to genotoxic agents, including anthracyclines and ionizing radiation. FKBP51 is a cochaperone with peptidyl-prolyl isomerase activity that regulates several biological processes through protein-protein interaction. There is increasing evidence that FKBP51 hyperexpression is associated with cancer and this protein has a relevant role in sustaining cell growth, malignancy, and resistance to therapy. There is also evidence that FKBP ligands are potent anticancer agents, in addition to their immunosuppressant activity. In particular, rapamycin and its analogs have shown antitumor activity across a variety of human cancers in clinical trials. Although, classically, rapamycin actions are ascribed to inhibition of mTOR, recent studies indicate FKBP51 is also an important molecular determinant of the drug’s anticancer activity. The aim of this article is to review the functions of FKBP51, especially in view of the recent findings that this protein is a potential oncogene when deregulated and a candidate target for signaling therapies against cancer.
Highlights
FK506 binding proteins (FKBP) belong to the family of immunophilins, which includes cyclophilins (Cyp) [1]
Its function is still far from being fully elucidated, there are clear data suggesting this immunophilin plays an active role in cell proliferation in both the physiologic conditions of cell growth and differentiation [28,29,30,31] and in pre-neoplastic [3335] and neoplastic diseases [6,12]
Several lines of evidence support the conclusion that FK506 binding protein 51 (FKBP51) is a promising molecular therapeutic target in cancer [6,8,9,12,49]
Summary
FK506 binding proteins (FKBP) belong to the family of immunophilins, which includes cyclophilins (Cyp) [1]. At least 15 FKBPs have been identified and named to reflect their molecular weights [3] Members of this ubiquitous enzyme class are found in abundance in virtually all organisms and subcellular compartments. Organisms express many members of each family that encompass one or more PPIase domain, complemented with other functional polypeptide segments These segments or domains include tetratricopeptide repeat (TPR) motifs involved in proteinprotein interaction, EF-hand calcium-binding domain containing helix-loop-helix topology in which Ca2+ ions are coordinated within the loop, nucleic acid binding regions, transmembrane domain, and nuclear localization and endoplasmic reticulum signal sequences. The aim of this article is to review the functions of FKBP51 (schematically represented in Fig. 2) with a focus on the emerging role of this protein as a tumor promoter
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