Puma and to a Lesser Extent Noxa Are Suppressors of Myc-induced Lymphomagenesis

Cell Death Differ. 2009 May;16(5):684-96. doi: 10.1038/cdd.2008.195. Epub 2009 Jan 16.

Abstract

Evasion of apoptosis contributes importantly to c-Myc-induced tumorigenesis. The BH3-only Bcl-2 family members Puma and Noxa are critical pro-apoptotic transcriptional targets of p53, a major mediator of Myc-induced apoptosis and suppressor of Myc-induced tumorigenesis. Hence, we have explored the impact of their individual or combined loss on myc-driven lymphomagenesis. Notably, Puma deficiency both increased B-lineage cells and accelerated the development of B lymphoma, accompanied by leukaemia, but not of pre-B lymphoma. Noxa deficiency alone also increased B-lineage cells but did not accelerate lymphomagenesis. However, its deficiency combined with loss of one puma allele produced more rapid onset of both pre-B and B lymphomas than did loss of a single puma allele alone. Nevertheless, the acceleration evoked by loss of both genes was not as marked as that caused by p53 heterozygosity. These results show that Puma imposes a significant, and Noxa a minor barrier to c-Myc-driven lymphomagenesis. They also indicate that additional BH3-only proteins probably also drive Myc-induced apoptosis and that non-apoptotic functions of p53 may contribute substantially to its tumour suppressor role.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Precursor Cells, B-Lymphoid / metabolism
  • Precursor Cells, B-Lymphoid / pathology
  • Proto-Oncogene Proteins c-bcl-2 / deficiency
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*

Substances

  • Apoptosis Regulatory Proteins
  • PUMA protein, mouse
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins