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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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

Rosa Puca1, Lavinia Nardinocchi, Hilah Gal

  • 1Molecular Oncogenesis Laboratory and Preclinical Experimental Laboratory, Regina Elena Cancer Institute, Rome, Italy.

Cancer Research
|May 17, 2008
PubMed

Insights

Homeodomain-interacting protein kinase-2 (HIPK2) is crucial for wild-type p53 (wtp53) function. Low HIPK2 causes wtp53 misfolding, impairing its tumor-suppressing activity, but zinc can restore function.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Oncology

Background:

  • TP53 gene mutations occur in about half of all cancers.
  • Wild-type p53 (wtp53) function can be compromised by other alterations.
  • Homeodomain-interacting protein kinase-2 (HIPK2) positively regulates p53's tumor-suppressing activity.

Purpose of the Study:

  • To investigate the role of HIPK2 in maintaining wtp53 transactivation activity.
  • To explore the impact of HIPK2 knockdown on wtp53 function and conformation.
  • To evaluate the therapeutic potential of zinc supplementation in restoring wtp53 activity.

Main Methods:

  • Microarray analysis to assess target gene activation in HIPK2-knockdown cells.
  • p53 immunoprecipitation with conformation-specific antibodies to detect misfolding.
  • In vivo and in vitro experiments using zinc supplementation and Adriamycin treatment.
  • Bioinformatics analysis of colon cancer patient data.

Main Results:

  • Stable knockdown of HIPK2 (HIPK2i) led to wtp53 misfolding, impairing DNA binding and target gene transcription.
  • Zinc supplementation restored wtp53 conformation, DNA binding, and transcription in HIPK2i cells.
  • Combination therapy with zinc and Adriamycin suppressed tumor growth in vivo.
  • Low HIPK2 expression in wtp53-expressing colon tumors is associated with poor patient survival.

Conclusions:

  • HIPK2 plays a critical role in maintaining the transactivation activity of wtp53.
  • HIPK2 deficiency leads to wtp53 misfolding and loss of tumor-suppressive function.
  • Zinc supplementation represents a potential therapeutic strategy to restore wtp53 function in HIPK2-deficient cancers.

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