PU.1 binding to the p53 family of tumor suppressors impairs their transcriptional activity

Oncogene. 2008 May 29;27(24):3489-93. doi: 10.1038/sj.onc.1211004. Epub 2008 Jan 14.

Abstract

The transcription factor PU.1 is essential for terminal myeloid differentiation, B- and T-cell development, erythropoiesis and hematopoietic stem cell maintenance. PU.1 functions as oncogene in Friend virus-induced erythroleukemia and as tumor suppressor in acute myeloid leukemias. Moreover, Friend virus-induced erythroleukemia requires maintenance of PU.1 expression and the disruption of p53 function greatly accelerates disease progression. It has been hypothesized that p53-mediated expression of the p21(Cip1) cell cycle inhibitor during differentiation of pre-erythroleukemia cells promotes selection against p53 function. In addition to the blockage of erythroblast differentiation provided by increased levels of PU.1, we propose that PU.1 alters p53 function. We demonstrate that PU.1 reduces the transcriptional activity of the p53 tumor suppressor family and thus inhibits activation of genes important for cell cycle regulation and apoptosis. Inhibition is mediated through binding of PU.1 to the DNA-binding and/or oligomerization domains of p53/p73 proteins. Lastly, knocking down endogenous PU.1 in p53 wild-type REH B-cell precursor leukemia cells leads to increased expression of the p53 target p21(Cip1).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Immunoprecipitation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Isoforms
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / pharmacology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription, Genetic*
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Trans-Activators
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • p73 protein, human
  • proto-oncogene protein Spi-1