Reversible dysfunction of wild-type p53 following homeodomain-interacting protein kinase-2Kn ockdown

Rosa Puca, Lavinia Nardinocchi, Hilah Gal, Gideon Rechavi, Ninette Amariglio, Eytan Domany, Daniel A. Notterman, Marco Scarsella, Carlo Leonetti, Ada Sacchi, Giovanni Blandino, David Givol, Gabriella D'Orazi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3707-3714
Number of pages8
JournalCancer Research
Volume68
Issue number10
DOIs
Publication statusPublished - May 15 2008

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Homeodomain Proteins
Protein Kinases
Neoplasms
Microarray Analysis
Doxorubicin
Colonic Neoplasms
Transcriptional Activation
Zinc
Genes
Antibodies
p53 Genes
Computational Biology
Immunoprecipitation
Heterografts
Nude Mice
Cell Line
Mutation
Survival
DNA
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Reversible dysfunction of wild-type p53 following homeodomain-interacting protein kinase-2Kn ockdown. / Puca, Rosa; Nardinocchi, Lavinia; Gal, Hilah; Rechavi, Gideon; Amariglio, Ninette; Domany, Eytan; Notterman, Daniel A.; Scarsella, Marco; Leonetti, Carlo; Sacchi, Ada; Blandino, Giovanni; Givol, David; D'Orazi, Gabriella.

In: Cancer Research, Vol. 68, No. 10, 15.05.2008, p. 3707-3714.

Research output: Contribution to journalArticle

Puca, R, Nardinocchi, L, Gal, H, Rechavi, G, Amariglio, N, Domany, E, Notterman, DA, Scarsella, M, Leonetti, C, Sacchi, A, Blandino, G, Givol, D & D'Orazi, G 2008, 'Reversible dysfunction of wild-type p53 following homeodomain-interacting protein kinase-2Kn ockdown', Cancer Research, vol. 68, no. 10, pp. 3707-3714. https://doi.org/10.1158/0008-5472.CAN-07-6776
Puca, Rosa ; Nardinocchi, Lavinia ; Gal, Hilah ; Rechavi, Gideon ; Amariglio, Ninette ; Domany, Eytan ; Notterman, Daniel A. ; Scarsella, Marco ; Leonetti, Carlo ; Sacchi, Ada ; Blandino, Giovanni ; Givol, David ; D'Orazi, Gabriella. / Reversible dysfunction of wild-type p53 following homeodomain-interacting protein kinase-2Kn ockdown. In: Cancer Research. 2008 ; Vol. 68, No. 10. pp. 3707-3714.
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AU - Amariglio, Ninette

AU - Domany, Eytan

AU - Notterman, Daniel A.

AU - Scarsella, Marco

AU - Leonetti, Carlo

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