XDepletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-Null tumors Academic Article uri icon

Overview

MeSH Major

  • Breast Neoplasms
  • Phosphotransferases (Alcohol Group Acceptor)
  • Tumor Suppressor Protein p53

abstract

  • Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A(-/-), PIP4K2B(+/-), and TP53(-/-) mice were viable and had a dramatic reduction in tumor formation compared to TP53(-/-) littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.

publication date

  • November 7, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4070383

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2013.09.057

PubMed ID

  • 24209622

Additional Document Info

start page

  • 844

end page

  • 57

volume

  • 155

number

  • 4