PRAM-1 Is a Novel Adaptor Protein Regulated by Retinoic Acid (RA) and Promyelocytic Leukemia (PML)-RA Receptor α in Acute Promyelocytic Leukemia Cells

• Published in: The Journal of biological chemistry 2001-06, Vol.276 (25), p.22375-22381
• Main Authors: Moog-Lutz, Christel, Peterson, Erik J., Lutz, Pierre G., Eliason, Steve, Cavé-Riant, Florence, Singer, Andrew, Di Gioia, Yolande, Dmowski, Sally, Kamens, Joanne, Cayre, Yvon E., Koretzky, Gary
• Format: Article
• Language: English
• Subjects: adaptor protein; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Base Sequence; Cell Differentiation; chromosome 15; chromosome 17; Cloning, Molecular; DNA, Complementary; Gene Expression Regulation, Neoplastic - drug effects; Humans; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Life Sciences; Molecular Sequence Data; Neoplasm Proteins - physiology; Oncogene Proteins, Fusion - physiology; PML-RAR^a protein; PRAM-1 gene; PRAM-1 protein; Proteins - chemistry; Proteins - genetics; Proteins - metabolism; retinoic acid receptor ^a; RNA, Messenger - genetics; Tretinoin - pharmacology; Tumor Cells, Cultured; U937 Cells
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M011683200

The t(15;17) translocation, found in 95% of acute promyelocytic leukemia, encodes a promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) fusion protein. Complete remission of acute promyelocytic leukemia can be obtained by treating patients with all-trans retinoic acid, and PML-RARα plays a major role in mediating retinoic acid effects in leukemia cells. A main model proposed for acute promyelocytic leukemia is that PML-RARα exerts its oncogenic effects by repressing the expression of retinoic acid-inducible genes critical to myeloid differentiation. By applying subtraction cloning to acute promyelocytic leukemia cells, we identified a retinoic acid-induced gene, PRAM-1 (PML-RARα target gene encoding anAdaptor Molecule-1), which encodes a novel adaptor protein sharing structural homologies with the SLAP-130/fyb adaptor. PRAM-1 is expressed and regulated during normal human myelopoiesis. In U937 myeloid precursor cells, PRAM-1 expression is inhibited by expression of PML-RARα in the absence of ligand andde novo superinduced by retinoic acid. PRAM-1 associates with other adaptors, SLP-76 and SKAP-55HOM, in myeloid cell lines and with protein tyrosine kinase lyn. By providing the first evidence that PML-RARα dysregulates expression of an adaptor protein, our data open new insights into signaling events that are disrupted during transformation by PML-RARα and induced by retinoic acid duringde novo differentiation of acute promyelocytic leukemia cells. AJ272324