Abstract
Cyclin-dependent kinase inhibitors p16INK4a and p15INK4b, encoded by the CDKN2A and B loci, play an important role in negative regulation of the cell cycle. Furthermore, p19ARF also encoded by the CDKN2A locus, has been shown to regulate positively the p53 pathway leading to growth arrest and apoptosis. All three genes have been inactivated in human tumors. In myeloid cells, p15INK4b mRNA is upregulated during cytokine-induced differentiation and/or growth arrest, and hypermethylation of the p15INK4b gene promoter region is a common event in acute myeloid leukemia. In the present study, we examined murine monocyte/macrophage tumors with deregulated c-myc for evidence of Ink4 gene inactivation. p15Ink4b mRNA and protein were detected in the majority of leukemias, and p16Ink4a mRNA and protein were highly expressed in two of them. pRb was in a hypophosphorylated state in most of the neoplasms indicating that the Cdk inhibitors that were expressed in the cells were functional. The observed expression of p15Ink4b is inconsistent with their proliferation state, although it might be expected to be expressed owing to the maturity of the cells. These data suggest, therefore, that deregulated c-Myc bypasses the pRb restriction point and cell cycle arrest in these tumors. An examination of p19Arf exons revealed deletions of the gene in up to 94% of the tumors. Since this gene shares exon 2 with p16Ink4a, it is often difficult to determine which gene is the relevant tumor suppressor. However, the loss of only the p19Arf-specific exon 1β was observed in a tumor that had normal p16Ink4a protein expression. In addition, the p19Arf-specific exon was deleted in another tumor that expressed a functional chimeric protein, p15Ex1–p16Ex2-3; it was demonstrated here that this fusion protein is capable of inducing G1 arrest. These data overall supports the hypothesis that the critical inactivation event in these hematopoietic neoplasms is elimination of p19Arf, and not Ink4 function.
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Acknowledgements
We thank Dan Lieberman and Beverly Mock for kindly providing the p15Ink4b and p16Ink4a cDNA probes. We also thank Mark Miller for analysis of the sequencing reactions and Barbara Taylor for cell cycle analysis on the flow cytometer.
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Haviernik, P., Schmidt, M., Hu, X. et al. Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc. Oncogene 22, 1600–1610 (2003). https://doi.org/10.1038/sj.onc.1206268
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DOI: https://doi.org/10.1038/sj.onc.1206268
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