Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer

Prakash Kulkarni, A. Dunker, Keith Weninger, John Orban

Research output: Contribution to journalReview article

9 Citations (Scopus)

Abstract

Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCA). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCA, especially patients with low-risk disease.

Original languageEnglish (US)
Pages (from-to)695-703
Number of pages9
JournalAsian Journal of Andrology
Volume18
Issue number5
DOIs
StatePublished - Sep 1 2016

Fingerprint

Testicular Neoplasms
Prostate
Prostatic Neoplasms
Antigens
Genes
jun Genes
Therapeutics
Intrinsically Disordered Proteins
Transcription Factor AP-1
Heat-Shock Proteins
Computational Biology
Transcriptional Activation
DNA Damage
Reactive Oxygen Species
Protein Isoforms
Phosphorylation
Pathology
Messenger RNA
Peptides

Keywords

  • c-Jun-AP-1
  • cancer/testis antigen
  • homeodomain.interacting protein 1
  • intrinsically disordered protein
  • prostate cancer
  • prostate-associated Gene 4
  • protein interaction networks

ASJC Scopus subject areas

  • Urology

Cite this

Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer. / Kulkarni, Prakash; Dunker, A.; Weninger, Keith; Orban, John.

In: Asian Journal of Andrology, Vol. 18, No. 5, 01.09.2016, p. 695-703.

Research output: Contribution to journalReview article

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abstract = "Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCA). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCA, especially patients with low-risk disease.",
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