PRAM-1 Is a Novel Adaptor Protein Regulated by Retinoic Acid (RA) and Promyelocytic Leukemia (PML)-RA Receptor α in Acute Promyelocytic Leukemia Cells*
- Christel Moog-LutztOaFNbFNc,
- Erik J. PetersonFNb,tOd,tOe,tOfFNg,
- Pierre G. LutztOaFNb,
- Steve EliasontOd,
- Florence Cavé-RianttOa,
- Andrew SingertOd,
- Yolande Di GioiatOa,
- Sally DmowskitOd,tOf,
- Joanne KamenstOh,
- Yvon E. CayretOa,iFNjFNk and
- Gary KoretzkytOd,tOfFNj
- From the tOaUnité INSERM 417, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France, the Departments of tOdPathology and tOeMedicine and the tOfAbramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the tOhBASF Bioresearch Corporation, Worcester, Massachusetts 01605, and the iDepartment of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5541
Abstract
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.
- APL
- acute promyelocytic leukemia
- PML
- promyelocytic leukemia
- RA
- retinoic acid
- RARα
- RA receptor α
- ATRA
- all-trans retinoic acid
- PTK
- protein tyrosine kinase
- SH
- Src homology domain
- bp
- base pair(s)
- RACE
- rapid amplification of cDNA ends
- PCR
- polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- PAGE
- polyacrylamide gel electrophoresis
- Received December 26, 2000.
- Revision received March 21, 2001.
- The American Society for Biochemistry and Molecular Biology, Inc.
