PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells.
The t(15;17) translocation, found in 95% of acute promyelocytic leukemia, encodes a promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) fusion protein. Complete remission of acute promyelocytic leukemia can be obtained by treating patients with all-trans retinoic acid, and PML-RARalpha plays a major role in mediating retinoic acid effects in leukemia ... cells. A main model proposed for acute promyelocytic leukemia is that PML-RARalpha 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-RARalpha target gene encoding an Adaptor 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-RARalpha in the absence of ligand and de 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-RARalpha dysregulates expression of an adaptor protein, our data open new insights into signaling events that are disrupted during transformation by PML-RARalpha and induced by retinoic acid during de novo differentiation of acute promyelocytic leukemia cells.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Base Sequence, Cell Differentiation, Cloning, Molecular, DNA, Complementary, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Promyelocytic, Acute, Molecular Sequence Data, Neoplasm Proteins, Oncogene Proteins, Fusion, Proteins, RNA, Messenger, Tretinoin, Tumor Cells, Cultured, U937 Cells
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Base Sequence, Cell Differentiation, Cloning, Molecular, DNA, Complementary, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Promyelocytic, Acute, Molecular Sequence Data, Neoplasm Proteins, Oncogene Proteins, Fusion, Proteins, RNA, Messenger, Tretinoin, Tumor Cells, Cultured, U937 Cells
J. Biol. Chem.
Date: Jun. 22, 2001
PubMed ID: 11301322
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