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Received for publication August 12, 2004.
Revised October 15, 2004.
Accepted for publication October 15, 2004.
All-trans retinoic acid (ATRA) induces differentiation of promyelocytic leukemia cells, but the mechanisms by which cellular differentiation leads to apoptosis are not well understood. Studies were done to address the question whether ATRA-induced apoptosis is a consequence of destabilization of bcl-2 mRNA and decreased cellular levels of the anti-apoptotic protein, bcl-2. ATRA induced differentiation of HL-60 cells along the granulocytic pathway within 48 hr. The half-lives of bcl-2 mRNA in HL-60 cells incubated with ATRA for 48 hr or 72 hr were reduced to 39 % and 7 % of the corresponding untreated control values, respectively. Cellular differentiation was accompanied by downregulation of the cytoplasmic levels of nucleolin, a bcl-2 mRNA stabilizing protein. Binding of a bcl-2 mRNA instability element (ARE-1)to nucleolin in S100 extracts from ATRA-treated cells was decreased to 15 % of control within 72 hr. The decay of 5' capped, polyadenylated bcl-2 mRNA transcripts containing ARE-1 was more rapid in S100 extracts from ATRA-treated cells compared to untreated cells. However, when recombinant nucleolin was added to extracts of ATRA-treated cells, the rate of bcl-2 mRNA decay was similar to the rate in extracts of untreated cells. These results provide evidence that ATRA-induced apoptosis is a consequence of cellular differentiation, which leads to nucleolin downregulation and bcl-2 mRNA instability
Key words:
Apoptosis, Mechanisms of cell killing/apoptosis
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