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PMID:20181722

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Citation

Tavassoli, P, Wafa, LA, Cheng, H, Zoubeidi, A, Fazli, L, Gleave, M, Snoek, R and Rennie, PS (2010) TAF1 differentially enhances androgen receptor transcriptional activity via its N-terminal kinase and ubiquitin-activating and -conjugating domains. Mol. Endocrinol. 24:696-708

Abstract

Aberrant expression of androgen receptor (AR) coregulators has been linked to progression of prostate cancers to castration resistance. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. Glutathione S-transferase pulldown assays established that TAF1 bound through its acetylation and ubiquitin-activating/conjugating domains (E1/E2) directly to the AR N terminus. Coimmunoprecipitation and ChIP assays revealed colocalization of TAF1 and AR on the prostate-specific antigen promoter/enhancer in prostate cancer cells. With respect to modulation of AR activity, overexpression of TAF1 enhanced AR activity severalfold, whereas small interfering RNA knockdown of TAF1 significantly decreased AR transactivation. Although full-length TAF1 showed enhancement of both AR and some generic gene transcriptional activity, selective AR coactivator activity by TAF1 was demonstrated in transactivation experiments using cloned N-terminal kinase and E1/E2 functional domains. In keeping with AR coactivation by the ubiquitin-activating and -conjugating domain, TAF1 was found to greatly increase the cellular amount of polyubiquitinated AR. In conclusion, our results indicate that increased TAF1 expression is associated with progression of human prostate cancers to the lethal castration-resistant state. Because TAF1 is a coactivator of AR that binds and enhances AR transcriptional activity, its overexpression could be part of a compensatory mechanism adapted by cancer cells to overcome reduced levels of circulating androgens.

Links

PubMed PMC5417532 Online version:10.1210/me.2009-0229

Keywords

Blotting, Western; Cell Line, Tumor; Histone Acetyltransferases; Humans; Immunoprecipitation; In Vitro Techniques; Male; Prostatic Neoplasms/genetics; Prostatic Neoplasms/metabolism; Protein Binding; RNA, Small Interfering; Receptors, Androgen/genetics; Receptors, Androgen/metabolism; TATA-Binding Protein Associated Factors/genetics; TATA-Binding Protein Associated Factors/metabolism; Transcription Factor TFIID/genetics; Transcription Factor TFIID/metabolism; Transcriptional Activation; Two-Hybrid System Techniques

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ANDR

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ANDR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21675

F

  • has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

RAT:ANDR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21675

F

Seeded From UniProt

complete

HUMAN:TAF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15207

F

  • has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:TAF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q00987

F

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:0000209: protein polyubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:TAF1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

  • exists_during:(GO:0071383)
  • coincident_with:(SO:0001668)|exists_during(GO:0071383)
  • coincident_with:(SO:0000165)

Seeded From UniProt

complete

HUMAN:TAF1

enables

GO:0016922: nuclear receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P10275

F

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:2000825: positive regulation of androgen receptor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAF1

enables

GO:0061631: ubiquitin conjugating enzyme activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:MDM2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21675

F

Seeded From UniProt

complete

HUMAN:MDM2

involved_in

GO:0036369: transcription factor catabolic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

  • has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:ANDR

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • part_of:(GO:0071383)
  • regulates_transcription_of:(ENSEMBL:ENSG00000142515)

Seeded From UniProt

complete

HUMAN:ANDR

enables

GO:0001091: RNA polymerase II general transcription initiation factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21675

F

Seeded From UniProt

complete

HUMAN:TAF1

enables

GO:0035257: nuclear hormone receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P10275

F

Seeded From UniProt

complete

HUMAN:TAF1

part_of

GO:0000790: nuclear chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

  • exists_during:(GO:0071383)
  • coincident_with:(ENSEMBL:ENSG00000142515)
  • coincident_with:(SO:0001668)|exists_during(GO:0071383)
  • coincident_with:(ENSEMBL:ENSG00000142515)
  • coincident_with:(SO:0000165)

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:2000825: positive regulation of androgen receptor activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • part_of:(GO:0071383)
  • has_regulation_target:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:0036369: transcription factor catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:0046777: protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAF1

enables

GO:0061631: ubiquitin conjugating enzyme activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:TAF1

involved_in

GO:0000209: protein polyubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

HUMAN:MDM2

involved_in

GO:0036369: transcription factor catabolic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

has_input:(UniProtKB:P10275)

Seeded From UniProt

complete

Notes

See also

References

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