Abstract
The PML gene is fused to the retinoic acid receptor alpha (RARalpha) gene in chromosomal translocations associated with acute promyelocytic leukemia (APL). Ablation of murine PML protein by homologous recombination revealed that PML regulates hemopoietic differentiation and controls cell growth and tumorigenesis. PML function was essential for the tumor-growth-suppressive activity of retinoic acid (RA) and for its ability to induce terminal myeloid differentiation of precursor cells. PML was needed for the RA-dependent transactivation of the p21WAF1/CIP1 gene, which regulates cell cycle progression and cellular differentiation. These results indicate that PML is a critical component of the RA pathway and that disruption of its activity by the PML-RARalpha fusion protein may be important in APL pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Cell Differentiation / drug effects
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Cell Division*
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Cell Transformation, Neoplastic
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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Female
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Fibroblasts / cytology
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Gene Targeting
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Granulocytes / cytology
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Hematopoiesis
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Hematopoietic Stem Cells / cytology
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Leukemia, Promyelocytic, Acute / pathology
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Male
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Mice
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Monocytes / cytology
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasms, Experimental / etiology
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Nuclear Proteins*
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Oncogene Proteins, Fusion / physiology
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Promyelocytic Leukemia Protein
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcriptional Activation
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Tretinoin / pharmacology
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Tretinoin / physiology*
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Tumor Suppressor Proteins
Substances
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Transcription Factors
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Tumor Suppressor Proteins
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Tretinoin