Mutations in the p53 and SCID genes cooperate in tumorigenesis

Mariana Nacht, Andreas Strasser, Yvonne R. Chan, Alan W. Harris, Mark Schlissel, Roderick T. Bronson, Tyler Jacks

Research output: Contribution to journalArticlepeer-review

164 Scopus citations

Abstract

DNA damage can cause mutations that contribute to cellular transformation and tumorigenesis. The p53 tumor suppressor acts to protect the organism from DNA damage by inducing either G1 arrest to facilitate DNA repair or by activating physiological cell death (apoptosis). Consistent with this critical function of p53, mice lacking p53 are predisposed to developing tumors, particularly lymphoma. The severe combined immune deficiency (scid) locus encodes the catalytic subunit of DNA protein kinase (DNA-PKcs), a protein complex that has a role in the cellular response to DNA damage. Cells from scid mice are hypersensitive to radiation and scid lymphocytes fail to develop from precursors because they are unable to properly join DNA-coding ends during antigen receptor gene rearrangement. We examined the combined effect of loss of p53 and loss of DNA-PKcs on lymphocyte development and tumorigenesis by generating p53(-/-) scid mice. Our data demonstrate that loss of p53 promotes T-cell development in scid mice but does not noticeably affect B lymphopoiesis. Moreover, scid cells are able to induce p53 protein expression and activate G1 arrest or apoptosis in response to ionizing radiation, indicating that DNA-PKcs is not essential for these responses to DNA damage. Furthermore, p53(-/-) scid double mutant mice develop lymphoma earlier than p53(-/-) littermates, demonstrating that loss of these two genes can cooperate in tumorigenesis. Collectively, these results provide evidence for an unsuspected role of p53 as a checkpoint regulator in early T-cell development and demonstrate that loss of an additional component of the cellular response to DNA damage can cooperate with loss of p53 in lymphomagenesis.

Original languageEnglish
Pages (from-to)2055-2066
Number of pages12
JournalGenes and Development
Volume10
Issue number16
DOIs
StatePublished - 1996
Externally publishedYes

Keywords

  • SCID
  • T-cell development
  • p53
  • tumorigenesis

Fingerprint

Dive into the research topics of 'Mutations in the p53 and SCID genes cooperate in tumorigenesis'. Together they form a unique fingerprint.

Cite this