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PMID:20395202

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Citation

Bowen, C and Gelmann, EP (2010) NKX3.1 activates cellular response to DNA damage. Cancer Res. 70:3089-97

Abstract

The prostate-specific tumor suppressor homeodomain protein NKX3.1 is inactivated by a variety of mechanisms in the earliest phases of prostate carcinogenesis and in premalignant regions of the prostate gland. The mechanisms by which NKX3.1 exercises tumor suppression have not been well elucidated. Here, we show that NKX3.1 affects DNA damage response and cell survival after DNA damage. NKX3.1 expression in PC-3 prostate cancer cells enhances colony formation after DNA damage but has minimal effect on apoptosis. NKX3.1 also diminishes and regulates total cellular accumulation of gammaH2AX. Endogenous NKX3.1 in LNCaP cells localizes to sites of DNA damage where it affects the recruitment of phosphorylated ATM and the phosphorylation of H2AX. Knockdown of NKX3.1 in LNCaP cells attenuates the acute responses of both ATM and H2AX phosphorylation to DNA damage and their subnuclear localization to DNA damage sites. NKX3.1 expression enhances activation of ATM as assayed by autophosphorylation at serine 1981 and activation of ATR as assayed by phosphorylation of CHK1. An inherited mutation of NKX3.1 that predisposes to early prostate cancer and attenuates in vitro DNA binding was devoid of the ability to activate ATM and to colocalize with gammaH2AX at foci of DNA damage. These data show a novel mechanism by which a homeoprotein can affect DNA damage repair and act as a tumor suppressor.

Links

PubMed Online version:10.1158/0008-5472.CAN-09-3138

Keywords

Apoptosis; Cell Cycle Proteins/metabolism; Cell Line, Tumor; Cell Nucleus/metabolism; DNA Damage; DNA Repair; Gene Expression Regulation, Neoplastic; Homeodomain Proteins/metabolism; Humans; Male; Mutation; Phosphorylation; Prostatic Neoplasms/metabolism; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases/metabolism; Signal Transduction; Transcription Factors/metabolism

Significance

Annotations

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

HUMAN:NKX31

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13315)
  • happens_during:(GO:2001022)|has_input(UniProtKB:Q13535)
  • happens_during:(GO:2001022)|has_input(UniProtKB:P16104)
  • happens_during:(GO:2001022)|has_input(UniProtKB:O14757)
  • happens_during:(GO:2001022)

Seeded From UniProt

complete

HUMAN:NKX31

located_in

GO:0090734: site of DNA damage

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0032880: regulation of protein localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13315)
  • happens_during:(GO:0006974)|has_input(UniProtKB:Q13535)
  • happens_during:(GO:0006974)|has_input(UniProtKB:P16104)
  • happens_during:(GO:0006974)

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:2001022: positive regulation of response to DNA damage stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:Q13315)
  • happens_during:(GO:2001022)|has_regulation_target(UniProtKB:Q13535)
  • happens_during:(GO:2001022)|has_regulation_target(UniProtKB:P16104)
  • happens_during:(GO:2001022)|has_regulation_target(UniProtKB:O14757)
  • happens_during:(GO:2001022)

Seeded From UniProt

complete

HUMAN:NKX31

part_of

GO:0090734: site of DNA damage

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0032880: regulation of protein localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:Q13315)
  • happens_during:(GO:0006974)|has_regulation_target(UniProtKB:Q13535)
  • happens_during:(GO:0006974)|has_regulation_target(UniProtKB:P16104)
  • happens_during:(GO:0006974)

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0014068: positive regulation of phosphatidylinositol 3-kinase signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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