Transcriptional repression by the promyelocytic leukemia protein, PML.
Acute promyelocytic leukemia is characterized by the presence of a t(15; 17) chromosomal translocation which results in the expression of a chimeric gene product, PMLRAR alpha, consisting of an N-terminal-truncated retinoic acid receptor-alpha fused to a C-terminal-truncated PML. Several structural features, and regions of homology to known transcription factors, suggest that PML may be involved in the regulation of gene expression. In this study we have analyzed the transcriptional regulatory activity of PML using chimeric GAL4/PML constructs and GAL4-responsive reporter plasmids. The data presented demonstrate that PML, when fused to the DNA-binding domain of GAL4 (GAL4/PML), inhibits transcription from GAL4-responsive promoters. The magnitude of this repression is cell type and promoter dependent, and deletion studies show that the putative coiled-coil and part of the serine-rich regions of PML are required for this activity. These regions are also shown to be responsible for the repression of transcription activity from the EGFR promoter. The data presented also demonstrate that GAL4/PML can recruit PMLRAR alpha resulting in the retinoid-inducible transcriptional activation of a GAL4-responsive promoter, a function dependent on the presence of the coiled-coil region of PMLRAR alpha.
Vallian
S
S
Department of Molecular Medicine, Rayne Institute, King's College School of Medicine and Dentistry, London, United Kingdom.
Gäken
J A
JA
Trayner
I D
ID
Gingold
E B
EB
Kouzarides
T
T
Chang
K S
KS
Farzaneh
F
F
D000818:Animals; D002460:Cell Line; D019281:Dimerization; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D017384:Sequence Deletion; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D066246:ErbB Receptors