title: The emerging role of large immunophilin FK506 binding protein 51 in cancer.
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.
authors.affiliation: Department of Biochemistry and Medical Biotechnology, University of Naples "Federico II". Via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Romano
authors.forename: A
authors.initials: A
authors.lastname: Sorrentino
authors.forename: A L
authors.initials: AL
authors.lastname: Di Pace
authors.forename: G
authors.initials: G
authors.lastname: Nappo
authors.forename: C
authors.initials: C
authors.lastname: Mercogliano
authors.forename: M F
authors.initials: MF
authors.lastname: Romano
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
references.citation: Int Rev Cell Mol Biol. 2008;266:207-47
references.pmid: 18544495
references.citation: Blood. 2002 Oct 15;100(8):2932-40
references.pmid: 12351405
references.citation: Genes Dev. 2001 Jun 1;15(11):1383-92
references.pmid: 11390358
references.citation: Anticancer Res. 2003 Sep-Oct;23(5A):3657-61
references.pmid: 14666661
references.citation: Nature. 2010 Jun 17;465(7300):942-6
references.pmid: 20526321
references.citation: Biochemistry. 1986 Sep 9;25(18):5269-75
references.pmid: 3768347
references.citation: Annu Rev Immunol. 1996;14:649-83
references.pmid: 8717528
references.citation: Genes Dev. 2003 Sep 15;17(18):2205-32
references.pmid: 12975316
references.citation: Genes Dev. 2001 Apr 1;15(7):807-26
references.pmid: 11297505
references.citation: Proc Natl Acad Sci U S A. 1988 Jun;85(11):4051-5
references.pmid: 3131773
references.citation: Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S169-77
references.pmid: 14508096
references.citation: Annu Rev Cell Dev Biol. 1996;12:91-128
references.pmid: 8970723
references.citation: Eur J Cancer. 2007 Mar;43(5):935-46
references.pmid: 17320377
references.citation: PLoS Med. 2008 Jan 22;5(1):e8
references.pmid: 18215105
references.citation: Nature. 1995 Aug 17;376(6541):599-602
references.pmid: 7637810
references.citation: Nat Genet. 2004 Dec;36(12):1319-25
references.pmid: 15565110
references.citation: Mol Endocrinol. 1998 Mar;12(3):355-63
references.pmid: 9514153
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8
references.pmid: 11381127
references.citation: Science. 1992 Aug 14;257(5072):973-7
references.pmid: 1380182
references.citation: Science. 1996 Jul 12;273(5272):239-42
references.pmid: 8662507
references.citation: Science. 1998 Aug 14;281(5379):998-1001
references.pmid: 9703517
references.citation: Oncogene. 2001 Nov 1;20(50):7342-51
references.pmid: 11704864
references.citation: Exp Hematol. 2003 Jul;31(7):622-30
references.pmid: 12842707
references.citation: Oncogene. 2003 May 19;22(20):3113-22
references.pmid: 12789288
references.citation: Nat Med. 2001 Sep;7(9):1028-34
references.pmid: 11533706
references.citation: Curr Opin Pharmacol. 2011 Aug;11(4):288-93
references.pmid: 21565553
references.citation: Mol Vis. 2011;17:1172-81
references.pmid: 21617754
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2459-65
references.pmid: 16428340
references.citation: Nat Cell Biol. 2004 Feb;6(2):97-105
references.pmid: 14743216
references.citation: Biochemistry. 2007 Dec 11;46(49):14044-57
references.pmid: 18001136
references.citation: Curr Top Med Chem. 2003;3(12):1392-409
references.pmid: 12871171
references.citation: Cell Death Differ. 2010 Jan;17(1):145-57
references.pmid: 19696786
references.citation: Genes Dev. 2001 Nov 1;15(21):2852-64
references.pmid: 11691836
references.citation: Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):752-6
references.pmid: 8290595
references.citation: J Exp Ther Oncol. 2003 Mar-Apr;3(2):72-82
references.pmid: 12822513
references.citation: J Neurosci. 2010 Jan 13;30(2):591-9
references.pmid: 20071522
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10314-9
references.pmid: 11504908
references.citation: Nat Rev Drug Discov. 2005 Dec;4(12):988-1004
references.pmid: 16341064
references.citation: Anticancer Drugs. 1995 Aug;6(4):570-7
references.pmid: 7579561
references.citation: EMBO J. 2003 Mar 3;22(5):1158-67
references.pmid: 12606580
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11086-90
references.pmid: 7479942
references.citation: Mol Endocrinol. 1995 Apr;9(4):401-12
references.pmid: 7659084
references.citation: Stem Cell Rev Rep. 2009 Mar;5(1):36-50
references.pmid: 19224407
references.citation: Nat Rev Cancer. 2002 Apr;2(4):301-10
references.pmid: 12001991
references.citation: Mol Cell. 2007 Apr 13;26(1):75-87
references.pmid: 17434128
references.citation: Mol Endocrinol. 2000 Jul;14(7):939-46
references.pmid: 10894145
references.citation: Cell. 2000 Oct 13;103(2):253-62
references.pmid: 11057898
references.citation: Mol Cell. 2001 Feb;7(2):401-9
references.pmid: 11239468
references.citation: Mol Cell Biol. 1998 May;18(5):3034-43
references.pmid: 9566922
references.citation: Mol Cell Biol. 2010 Mar;30(5):1243-53
references.pmid: 20048054
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11422-7
references.pmid: 10500192
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11081-5
references.pmid: 7479941
references.citation: Neoplasia. 2008 Mar;10(3):235-43
references.pmid: 18320068
references.citation: Cancer Cell. 2009 Sep 8;16(3):259-66
references.pmid: 19732725
references.citation: Biochemistry. 2006 Dec 26;45(51):15776-84
references.pmid: 17176100
references.citation: Oncogene. 2010 Mar 18;29(11):1691-701
references.pmid: 20023700
references.citation: Blood. 2005 Aug 15;106(4):1400-6
references.pmid: 15878982
references.citation: Annu Rev Immunol. 1998;16:225-60
references.pmid: 9597130
references.citation: Nat Rev Cancer. 2008 Jul;8(7):545-54
references.pmid: 18511937
references.citation: Nat Rev Cancer. 2006 Sep;6(9):729-34
references.pmid: 16915295
references.citation: Eur J Cancer. 2004 Dec;40(18):2829-36
references.pmid: 15571967
references.citation: J Biol Chem. 2010 Sep 3;285(36):27900-10
references.pmid: 20605778
references.citation: Biochem Biophys Res Commun. 1997 Mar 17;232(2):437-43
references.pmid: 9125197
references.citation: J Mol Neurosci. 2008 Jul;35(3):307-22
references.pmid: 18563304
references.citation: Nature. 2010 Mar 11;464(7286):302-5
references.pmid: 20220849
references.citation: N Engl J Med. 2007 May 31;356(22):2271-81
references.pmid: 17538086
references.citation: J Biol Chem. 2003 May 9;278(19):17388-94
references.pmid: 12611898
references.citation: Cancer Res. 2005 Apr 15;65(8):3281-9
references.pmid: 15833861
references.citation: Mol Cell Biol. 1995 Aug;15(8):4395-402
references.pmid: 7542743
references.citation: Stem Cells. 2007 Mar;25(3):750-60
references.pmid: 17095706
references.citation: Proteins. 2008 Jul;72(1):197-208
references.pmid: 18214965
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15587-91
references.pmid: 9861013
references.citation: Science. 1995 Oct 13;270(5234):286-90
references.pmid: 7569976
references.citation: Nat Rev Cancer. 2007 Dec;7(12):961-7
references.pmid: 17972889
references.citation: J Biol Chem. 2011 Aug 26;286(34):30152-60
references.pmid: 21730050
references.citation: Mol Cell Biol. 1995 Feb;15(2):943-53
references.pmid: 7823959
references.citation: Cell Death Dis. 2010 Jul 15;1:e55
references.pmid: 21364660
references.citation: Nature. 1994 Jun 30;369(6483):756-8
references.pmid: 8008069
references.citation: J Urol. 2005 May;173(5):1772-7
references.pmid: 15821585
references.citation: Rev Physiol Biochem Pharmacol. 2003;148:105-50
references.pmid: 12698322