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The Cancer/Testis Antigen Prostate-associated Gene 4 (PAGE4) Is a Highly Intrinsically Disordered Protein

Zeng, Yu and He, Yanan and Yang, Fan and Mooney, Steven M. and Getzenberg, Robert H. and Orban, John and Kulkarni, Prakash (2011) The Cancer/Testis Antigen Prostate-associated Gene 4 (PAGE4) Is a Highly Intrinsically Disordered Protein. Journal of Biological Chemistry, 286 (16). pp. 13985-13994. ISSN 0021-9258. PMCID PMC3077599.

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The cancer/testis antigens (CTAs) are an important group of heterogeneous proteins that are predominantly expressed in the testis in the normal human adult but are aberrantly expressed in several types of cancers. Prostate-associated gene 4 (PAGE4) is a member of the CT-X family of CTAs that in addition to testis, is highly expressed in the fetal prostate, and may also play an important role both in benign and malignant prostate diseases. However, the function of this gene remains poorly understood. Here, we show that PAGE4 is a highly (100%) intrinsically disordered protein (IDP). The primary protein sequence conforms to the features of a typical IDP sequence and the secondary structure prediction algorithm metaPrDOS strongly supported this prediction. Furthermore, SDS-gel electrophoresis and analytical size exclusion chromatography of the recombinant protein revealed an anomalous behavior characteristic of IDPs. UV circular dichroism (CD) and NMR spectroscopy confirmed that PAGE4 is indeed a highly disordered protein. In further bioinformatic analysis, the PredictNLS algorithm uncovered a potential nuclear localization signal, whereas the algorithm DBS-Pred returned a 99.1% probability that PAGE4 is a DNA-binding protein. Consistent with this prediction, biochemical experiments showed that PAGE4 preferentially binds a GC-rich sequence. Silencing PAGE4 expression induced cell death via apoptosis and in mice carrying PCa xenografts, siRNA-mediated knockdown of the PAGE4 mRNA attenuated tumor growth in vivo. Furthermore, overexpressing PAGE4 protected cells from stress-induced death. To our knowledge, PAGE4 is the first example of a CTA that is an IDP with an anti-apoptotic function.

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Additional Information:© 2011 American Society for Biochemistry and Molecular Biology, Inc. Received for publication, December 9, 2010, and in revised form, February 23, 2011. Published, JBC Papers in Press, February 25, 2011. This work was supported, in whole or in part, by National Institutes of Health primates (19). Furthermore, members of the CT-X antigens in Grant SPORE 2P50CA058236-16 from the NCI, O’Brien Grant P50DK082998 from the NIDDK, and the Patrick C. Walsh Prostate Cancer Research Fund. We thank Prof. Pamela Bjorkman, Max Delbruck Professor of Biology, California Institute of Technology, for support and interest in this project and Prof. Gaetano Montelione, Department of Molecular Biology and Biochemistry, Rutgers University, for pointing out that PAGE4 may be an IDP.
Funding AgencyGrant Number
NIHSPORE 2P50CA058236-16
Patrick C. Walsh Prostate Cancer Research FundUNSPECIFIED
Subject Keywords:Circular Dichroism (CD); DNA-binding Protein; NMR; Protein Structure; Protein-Protein Interactions; Cancer/Testis Antigen; Intrinsically Disordered Protein; Prostate Cancer; Prostate-associated Gene 4; Stress-response Protein
Issue or Number:16
PubMed Central ID:PMC3077599
Record Number:CaltechAUTHORS:20110504-113210715
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23547
Deposited By: Jason Perez
Deposited On:05 May 2011 20:15
Last Modified:03 Oct 2019 02:47

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