Salomoni, Paolo;
Perrotti, Danilo;
Martinez, Robert;
Franceschi, Claudio;
Calabretta, Bruno
Resistance to apoptosis in CTLL-2 cells constitutively expressing c-Myb is associated with induction of BCL-2 expression and Myb-dependent regulation ofbcl-2 promoter activity
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Media type:
E-Article
Title:
Resistance to apoptosis in CTLL-2 cells constitutively expressing c-Myb is associated with induction of BCL-2 expression and Myb-dependent regulation ofbcl-2 promoter activity
Description:
<jats:p>c-Myb, the cellular homologue of the transforming gene of the avian myeloblastosis virus, is preferentially expressed in all hematopoietic lineages, including T and B lymphocyte lineages. In T lymphocytes, c-Myb expression appears to be required for cell cycle progression and proliferation. To further investigate the role of c-Myb in T cell proliferation and survival, interleukin (IL) 2-dependent CTLL-2 cells were transfected with a constitutively active<jats:italic>c-myb</jats:italic>or with a<jats:italic>c-myb</jats:italic>antisense construct able to down-regulate endogenous Myb levels, and the transfectants were assessed for proliferation and survival in low concentrations of IL-2 and for susceptibility to dexamethasone-induced apoptosis. Compared with control cells, CTLL-2 cells constitutively expressing c-Myb proliferate in low concentrations of IL-2 and are less susceptible to apoptosis induced by IL-2 deprivation or treatment with dexamethasone. In contrast, cells transfected with an antisense<jats:italic>c-myb</jats:italic>construct do not proliferate in low concentrations of IL-2 and undergo apoptosis upon IL-2 deprivation or dexamethasone treatment more rapidly than parental cells. Overexpression of c-Myb was accompanied by up-regulation of BCL-2 expression. In transient transfection assays, the murine<jats:italic>bcl-2</jats:italic>promoter was efficiently transactivated by c-Myb, but such effect was observed also in cells transfected with a DNA binding-deficient<jats:italic>c-myb</jats:italic>construct. Moreover, in gel retardation assays, a 38-bp oligomer in the shortest<jats:italic>bcl-2</jats:italic>promoter segment regulated by c-Myb formed a specific complex with nuclear extracts from c-Myb-transfected CTLL-2 cells. Thus, these results strongly suggest that c-Myb, in addition to regulating T cell proliferation, protects T lymphocytes from apoptosis by induction of BCL-2 expression, which involves a c-Myb-dependent mechanism of promoter regulation.</jats:p>