TY - JOUR
T1 - PRAM-1 Is a Novel Adaptor Protein Regulated by Retinoic Acid (RA) and Promyelocytic Leukemia (PML)-RA Receptor α in Acute Promyelocytic Leukemia Cells
AU - Moog-Lutz, Christel
AU - Peterson, Erik J.
AU - Lutz, Pierre G.
AU - Eliason, Steve
AU - Cavé-Riant, Florence
AU - Singer, Andrew
AU - Di Gioia, Yolande
AU - Dmowski, Sally
AU - Kamens, Joanne
AU - Cayre, Yvon E.
AU - Koretzky, Gary
PY - 2001/6/22
Y1 - 2001/6/22
N2 - 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 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-RARα 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-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 during de novo differentiation of acute promyelocytic leukemia cells.
AB - 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 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-RARα 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-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 during de novo differentiation of acute promyelocytic leukemia cells.
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U2 - 10.1074/jbc.M011683200
DO - 10.1074/jbc.M011683200
M3 - Article
C2 - 11301322
AN - SCOPUS:0035933709
SN - 0021-9258
VL - 276
SP - 22375
EP - 22381
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -