This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Puca, R. Articles by D'Orazi, G. Search for Related Content PubMed PubMed Citation Articles by Puca, R. Articles by D'Orazi, G.

Reversible Dysfunction of Wild-Type p53 following Homeodomain-Interacting Protein Kinase-2 Knockdown

¹ Molecular Oncogenesis Laboratory and ² Preclinical Experimental Laboratory, Regina Elena Cancer Institute; ³ Rome Oncogenomic Center, Rome, Italy; Departments of ⁴ Molecular Cell Biology and ⁵ Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; ⁶ Department of Pediatric Hemato-Oncology, Chaim Sheba Medical Center, Tel-Hashomer and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; ⁷ Department of Molecular Biology, Princeton University, Princeton, New Jersey; and ⁸ Department of Oncology and Neurosciences, University "G. D'Annunzio," Chieti, Italy

Requests for reprints: Gabriella D'Orazi, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. Phone: 39-06-52662542; Fax: 39-06-52662505; E-mail: gdorazi{at}unich.it.

Key Words: p53 transcription activity • protein misfolding • combination treatment • zinc • tumor growth

About half of cancers sustain mutations in the TP53 gene, whereas the other half maintain a wild-type p53 (wtp53) but may compromise the p53 response because of other alterations. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of p53 oncosuppressor function. Here, we show, by microarray analysis, that wtp53 lost the target gene activation following stable knockdown of HIPK2 (HIPK2i) in colon cancer cell line. Our data show that the stable knockdown of HIPK2 led to wtp53 misfolding, as detected by p53 immunoprecipitation with conformation-specific antibodies, and that p53 protein misfolding impaired p53 DNA binding and transcription of target genes. We present evidence that zinc supplementation to HIPK2i cells increased p53 reactivity to conformation-sensitive PAb1620 (wild-type conformation) antibody and restored p53 sequence-specific DNA binding in vivo and transcription of target genes in response to Adriamycin treatment. Finally, combination of zinc and Adriamycin suppressed tumor growth in vivo and activated misfolded p53 that induced its target genes in nude mice tumor xenografts derived from HIPK2i cells. Bioinformatics analysis of microarray data from colon cancer patients showed significant association of poor survival with low HIPK2 expression only in tumors expressing wtp53. These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53. [Cancer Res 2008;68(10):3707–13]

This article has been cited by other articles:

				G. Bon, S. E. Di Carlo, V. Folgiero, P. Avetrani, C. Lazzari, G. D'Orazi, M. F. Brizzi, A. Sacchi, S. Soddu, G. Blandino, et al. Negative Regulation of {beta}4 Integrin Transcription by Homeodomain-Interacting Protein Kinase 2 and p53 Impairs Tumor Progression Cancer Res., July 15, 2009; 69(14): 5978 - 5986. [Abstract] [Full Text] [PDF]