Transcriptional activation of the cyclin-dependent kinase inhibitor p21 by PML/RARalpha.
Acute promyelocytic leukemia (APL) is a result of clonal expansion of hematopoietic precursors blocked at the promyelocytic stage and is associated with a t(15;17) chromosomal translocation and the expression of the PML/RARalpha fusion protein. Treatment of APL cells with retinoic acid (RA) leads to complete remission by inducing growth arrest and differentiation of these cells into granulocytes. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 may be involved in terminal differentiation associated growth arrest. We showed in this study that PML/RARalpha increased the transcription of p21WAF1/CIP1 gene and the activation was further induced by RA treatment. Deletion analysis revealed a region upstream of the p21WAF1/CIP1 promoter that is required for transactivation by PML/RARalpha. Transient transfection of PML/RARalpha in cells increased the endogenous p21WAF1/CIP1 protein levels. These results suggest that the induction of APL cells differentiation by RA may be a result of the activation of p21WAF1/CIP1 by PML/RARalpha.
Yang
W L
WL
Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick 08901, USA.
Zeng
Y X
YX
El-Deiry
W S
WS
Nason-Burchenal
K
K
Dmitrovsky
E
E
Chin
K V
KV
D002457:Cell Extracts; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D002457:Cell Extracts; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D018844:Cyclin-Dependent Kinases