Absence of the steroid receptor coactivator-3 induces B-cell lymphoma

EMBO J. 2006 Jun 7;25(11):2453-64. doi: 10.1038/sj.emboj.7601106. Epub 2006 May 4.

Abstract

Steroid receptor coactivator 3 (SRC-3/ACTR/AIB-1/pCIP/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators that plays an important role in mammary gland growth, development, and tumorigenesis. We show that deletion of SRC-3 gene decreases platelet and increases lymphocytes numbers, leading to the development of malignant B-cell lymphomas upon aging. The expansion of the lymphoid lineage in SRC-3(-/-) mice is cell autonomous, correlates with an induction of proliferative and antiapoptotic genes secondary to constitutive NF-kappaB activation, and can be reversed by restoration of SRC-3 expression. NF-kappaB activation is explained by the degradation of IkappaB, consequent to increases in free IkappaB kinase, which is no longer inhibited by SRC-3. These results demonstrate that SRC-3 regulates lymphopoiesis and in combination with previous studies indicate that SRC-3 has vastly diverging effects on cell proliferation depending on the cellular context, ranging from proliferative and tumorigenic (breast) to antiproliferative (lymphoid cells) effects.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Blood Platelets / metabolism
  • Cell Proliferation
  • Female
  • Histone Acetyltransferases
  • Liver / cytology
  • Liver / metabolism
  • Liver / pathology
  • Lung / cytology
  • Lung / metabolism
  • Lung / pathology
  • Lymph Nodes / cytology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphocytes / cytology
  • Lymphocytes / metabolism*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism*
  • Lymphoma, B-Cell / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Nuclear Receptor Coactivator 3
  • Proto-Oncogene Proteins c-myb / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Spleen / cytology
  • Spleen / metabolism
  • Spleen / pathology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins c-myb
  • Proto-Oncogene Proteins c-myc
  • Trans-Activators
  • Histone Acetyltransferases
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3