Abstract
The PLZF gene was identified by its fusion with the RARalpha locus in a therapy resistant form of acute promyelocytic leukemia (APL) associated with the t(11;17)(q23;q21) translocation. Here we describe PLZF as a negative regulator of cell cycle progression ultimately leading to growth suppression. PLZF can bind and repress the cyclin A2 promoter while expression of cyclin A2 reverts the growth suppressed phenotype of myeloid cells expressing PLZF. In contrast RARalpha-PLZF, a fusion protein generated in t(11;17)(q23;q21)-APL activates cyclin A2 transcription and allows expression of cyclin A in anchorage-deprived NIH3T3 cells. Therefore, cyclin A2 is a candidate target gene for PLZF and inhibition of cyclin A expression may contribute to the growth suppressive properties of PLZF. Deregulation of cyclin A2 by RARalpha-PLZF may represent an oncogenic mechanism of this chimeric protein and contribute to the aggressive clinical phenotype of t(11;17)(q23;q21)-associated APL.
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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3T3 Cells
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Animals
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Cell Cycle / genetics*
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Chromosomes, Human, Pair 11
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Chromosomes, Human, Pair 17
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Cyclin A / metabolism*
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Cyclin-Dependent Kinases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Genetic Vectors
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Humans
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Interphase / genetics
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Kruppel-Like Transcription Factors
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Leukemia, Promyelocytic, Acute / genetics*
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Leukemia, Promyelocytic, Acute / metabolism
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Leukemia, Promyelocytic, Acute / pathology
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Mice
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Neoplasm Proteins / metabolism*
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Oncogene Proteins, Fusion / physiology*
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Promyelocytic Leukemia Zinc Finger Protein
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S Phase / genetics
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Translocation, Genetic
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Zinc Fingers / physiology
Substances
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Cyclin A
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DNA-Binding Proteins
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Kruppel-Like Transcription Factors
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Promyelocytic Leukemia Zinc Finger Protein
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Transcription Factors
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Zbtb16 protein, mouse
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ZBTB16 protein, human
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Cyclin-Dependent Kinases