Home LiteratureArticle Details
PMID: 14755308 Published · ppublish English Journal Article Review

Biological activities of HAP46/BAG-1. The HAP46/BAG-1 protein: regulator of HSP70 chaperones, DNA-binding protein and stimulator of transcription.

EMBO reports ·Vol. 5 ·No. 2 ·2004-02-00 ·Pages 148-53

Gehring U

Abstract

HAP46/BAG-1M and its isoforms affect the protein-folding activities of mammalian HSP70 chaperones. They interact with the ATP-binding domain of HSP70 or HSC70, leaving the substrate-binding site available for further interactions. Trimeric complexes can therefore form with, for example, transcription factors. Moreover, HAP46/BAG-1M and the larger isoform HAP50/BAG-1L bind to DNA non-specifically and enhance transcription in vitro and upon overexpression in intact cells. These factors are linked to positive effects on cell proliferation and survival. This review focuses on DNA-binding activity and transcriptional stimulation by HAP46/BAG-1M, and presents a molecular model for the underlying mechanism. It is proposed that transcription factors are recruited into complexes with HAP46/BAG-1M or HAP50/BAG-1L through HSP70/HSC70 and that response-element-bound complexes that contain HAP46/BAG-1M and/or HAP50/BAG-1L along with HSP70s target and affect the basal transcription machinery.

MeSH Terms
Animals Carrier Proteins/genetics,metabolism,physiology Cell Survival DNA-Binding Proteins/metabolism Gene Expression Regulation HSP70 Heat-Shock Proteins/genetics,metabolism Humans Neoplasms/metabolism Protein Folding Protein Isoforms/genetics,metabolism Protein Structure, Tertiary Receptors, Steroid/metabolism Transcription Factors/genetics,metabolism Transcriptional Activation Ubiquitin/chemistry,metabolism Up-Regulation/genetics
Chemicals
BCL2-associated athanogene 1 protein Carrier Proteins DNA-Binding Proteins HSP70 Heat-Shock Proteins Protein Isoforms Receptors, Steroid Transcription Factors Ubiquitin
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Gehring Ulrich
Universität Heidelberg, c/o Molekulare Evolution und Genomik, Im Neuenheimer Feld 230, D-69120 Heidelberg, Germany. [email protected]
References (49)
49 references, click to expand
  1. BAG-1 p50 isoform interacts with the vitamin D receptor and its cellular overexpression inhibits the vitamin D pathway.
    Exp Cell Res. 2001 Apr 15;265(1):167-73 PMID: 11281654
  2. Structural analysis of BAG1 cochaperone and its interactions with Hsc70 heat shock protein.
    Nat Struct Biol. 2001 Apr;8(4):349-52 PMID: 11276257
  3. Tuning of chaperone activity of Hsp70 proteins by modulation of nucleotide exchange.
    Nat Struct Biol. 2001 May;8(5):427-32 PMID: 11323718
  4. Transcriptional activation by the human Hsp70-associating protein Hap50.
    J Cell Sci. 2001 May;114(Pt 10):1839-45 PMID: 11329370
  5. Bag-1M accelerates nucleotide release for human Hsc70 and Hsp70 and can act concentration-dependent as positive and negative cofactor.
    J Biol Chem. 2001 Aug 31;276(35):32538-44 PMID: 11441021
  6. The carboxyl-terminal lobe of Hsc70 ATPase domain is sufficient for binding to BAG1.
    Biochem Biophys Res Commun. 2001 Dec 21;289(5):1099-105 PMID: 11741305
  7. Hsp70 chaperone machines.
    Adv Protein Chem. 2001;59:1-44 PMID: 11868269
  8. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome.
    J Biol Chem. 2002 Nov 29;277(48):45920-7 PMID: 12297498
  9. Down-regulation of Bcl-2-interacting protein BAG-1 confers resistance to anti-cancer drugs.
    Biochem Biophys Res Commun. 2003 Feb 14;301(3):798-803 PMID: 12565851
  10. Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the glucocorticoid receptor.
    J Biol Chem. 2003 Feb 14;278(7):4926-31 PMID: 12482863
  11. BAG-1: a multifunctional regulator of cell growth and survival.
    Biochim Biophys Acta. 2003 Mar 17;1603(2):83-98 PMID: 12618309
  12. Transcriptional stimulation by the DNA binding protein Hap46/BAG-1M involves hsp70/hsc70 molecular chaperones.
    Nucleic Acids Res. 2003 Apr 15;31(8):2209-16 PMID: 12682371
  13. Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.
    Mol Cell Biol. 2003 May;23(10):3477-86 PMID: 12724406
  14. BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway.
    Cancer Res. 2003 Jul 15;63(14):4150-7 PMID: 12874020
  15. The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription.
    Oncogene. 2003 Aug 7;22(32):4973-82 PMID: 12902980
  16. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity.
    Cell. 1995 Jan 27;80(2):279-84 PMID: 7834747
  17. A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning.
    Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11465-9 PMID: 8524784
  18. Cloning of cDNAs encoding the human BAG1 protein and localization of the human BAG1 gene to chromosome 9p12.
    Genomics. 1996 Aug 1;35(3):494-8 PMID: 8812483
  19. Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor beta c chain.
    Blood. 1996 Dec 1;88(11):4118-23 PMID: 8943845
  20. HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death.
    EMBO J. 1996 Nov 15;15(22):6205-12 PMID: 8947043
  21. BAG-1 modulates the chaperone activity of Hsp70/Hsc70.
    EMBO J. 1997 Aug 15;16(16):4887-96 PMID: 9305631
  22. Mammalian protein RAP46: an interaction partner and modulator of 70 kDa heat shock proteins.
    EMBO J. 1997 Sep 15;16(18):5483-90 PMID: 9312007
  23. GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1.
    EMBO J. 1997 Oct 15;16(20):6209-16 PMID: 9321400
  24. Proteins interacting with the molecular chaperone hsp70/hsc70: physical associations and effects on refolding activity.
    FEBS Lett. 1997 Nov 3;417(1):109-13 PMID: 9395086
  25. Mammalian cells express two differently localized Bag-1 isoforms generated by alternative translation initiation.
    Biochem J. 1997 Dec 15;328 ( Pt 3):807-13 PMID: 9396724
  26. BAG-1L protein enhances androgen receptor function.
    J Biol Chem. 1998 May 8;273(19):11660-6 PMID: 9565586
  27. p53-inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG-1.
    EMBO J. 1998 May 15;17(10):2736-47 PMID: 9582267
  28. RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis.
    J Biol Chem. 1998 Jun 5;273(23):14620-5 PMID: 9603979
  29. Interaction of BAG-1 with retinoic acid receptor and its inhibition of retinoic acid-induced apoptosis in cancer cells.
    J Biol Chem. 1998 Jul 3;273(27):16985-92 PMID: 9642262
  30. Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines.
    Cancer Res. 1998 Jul 15;58(14):3116-31 PMID: 9679980
  31. Human BAG-1/RAP46 protein is generated as four isoforms by alternative translation initiation and overexpressed in cancer cells.
    Oncogene. 1998 Aug 27;17(8):981-9 PMID: 9747877
  32. Interference between proteins Hap46 and Hop/p60, which bind to different domains of the molecular chaperone hsp70/hsc70.
    Mol Cell Biol. 1998 Nov;18(11):6238-44 PMID: 9774640
  33. An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.
    J Biol Chem. 1999 Jan 8;274(2):781-6 PMID: 9873016
  34. Structure of a new crystal form of human Hsp70 ATPase domain.
    Acta Crystallogr D Biol Crystallogr. 1999 May;55(Pt 5):1105-7 PMID: 10216320
  35. Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants.
    Oncogene. 1999 Aug 12;18(32):4546-53 PMID: 10467399
  36. The hsp70-associating protein Hap46 binds to DNA and stimulates transcription.
    Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10194-9 PMID: 10468585
  37. Bag1 functions in vivo as a negative regulator of Hsp70 chaperone activity.
    Mol Cell Biol. 2000 Feb;20(3):1083-8 PMID: 10629065
  38. The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome.
    J Biol Chem. 2000 Feb 18;275(7):4613-7 PMID: 10671488
  39. Isoform-specific expression of BAG-1 in mouse development.
    Mech Dev. 2000 Mar 1;91(1-2):355-9 PMID: 10704864
  40. Resistance to apoptosis is correlated with the reduced caspase-3 activation and enhanced expression of antiapoptotic proteins in human cervical multidrug-resistant cells.
    Biochem Biophys Res Commun. 2000 Apr 13;270(2):415-20 PMID: 10753639
  41. Distinct isoforms of the cofactor BAG-1 differentially affect Hsc70 chaperone function.
    J Biol Chem. 2000 May 19;275(20):14817-23 PMID: 10809723
  42. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia.
    Blood. 2000 Jul 15;96(2):393-7 PMID: 10887097
  43. Human DnaJ homologs dj2 and dj3, and bag-1 are positive cochaperones of hsc70.
    J Biol Chem. 2000 Aug 11;275(32):24728-34 PMID: 10816573
  44. Hsp70-RAP46 interaction in downregulation of DNA binding by glucocorticoid receptor.
    EMBO J. 2000 Dec 1;19(23):6508-16 PMID: 11101523
  45. BAG1L enhances trans-activation function of the vitamin D receptor.
    J Biol Chem. 2000 Dec 29;275(52):40749-56 PMID: 10967105
  46. Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors.
    Science. 2001 Feb 23;291(5508):1553-7 PMID: 11222862
  47. Bag1-Hsp70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth.
    Nat Cell Biol. 2001 Mar;3(3):276-82 PMID: 11231577
  48. Dissection of the ATP-binding domain of the chaperone hsc70 for interaction with the cofactor Hap46.
    J Biol Chem. 2001 Mar 30;276(13):10178-84 PMID: 11121403
  49. Structure-function analysis of Bag1 proteins. Effects on androgen receptor transcriptional activity.
    J Biol Chem. 2001 Apr 20;276(16):12718-24 PMID: 11278763
Article Info
Journal
EMBO reports
Abbr.
EMBO Rep
ISSN
1469-221X
DOI
10.1038/sj.embor.7400083
Email
[email protected]
Published
2004-02-00
Pages
148-53
Language
English
Region
England
NLM ID
100963049
PMCID
PMC1298994
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.embor.7400083 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2