Bert W. O'malley

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

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‐κB activation, and can be reversed by restoration of SRC‐3 expression. NF‐κB activation is explained by the degradation of IκB, consequent to increases in free IκB 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.

Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology

Transcriptional coactivators have evolved as an important new class of functional proteins that participate with virtually all transcription factors and nuclear receptors (NRs) to intricately regulate gene expression in response to a wide variety of environmental cues. Recent findings have highlighted that coactivators are important for almost all biological functions, and consequently, genetic defects can lead to severe pathologies. Drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases.