Abstract
Elevation of the cyclin-dependent kinase (cdk) inhibitor, p27(kip1) is necessary for Interleukin (IL)-4-mediated growth arrest of human low grade astrocytoma (RTLGA) cells and occurs at 24 h of treatment. Pathways involved in IL-4 alteration of p27(kip1) are unknown, however. Here we investigated whether other cdk inhibitors contributed to the actions of IL-4 on RTLGA cells. By 12 h of IL-4 treatment, both cdk4 and cdk2 kinase activities against the retinoblastoma protein (pRb) were reduced and nuclear entry of pRb was prohibited. Twelve-hour cdk complexes contained elevated p21(waf1/cip1) but not p27(kip1), p15(ink4B) or p16(ink4A). IL-4 increased p21(waf1/cip1) but not p27(kip1) mRNA levels, and stimulated luciferase activity of a p21(waf1/cip1) promoter-luciferase reporter. In p53-mutant WITG3 cells, IL-4 did not alter p21(waf1/cip1) mRNA and promoter-luciferase activity or p27(kip1) protein, suggesting a need for functional p53. STAT6 phosphorylation by IL-4, however, occurred in both p53-mutant WITG3 and p53-functional RTLGA cells. Pre-treatment of RTLGA with anti-sense but not missense p21(waf1/cip1) oligonucleotide prior to IL-4: (a) restored cdk activities; (b) reduced cdk4-associated p21(waf1/cip1) levels; (c) prevented p27(kip1) elevation; and (d) reversed growth arrest. These results are the first to suggest that p21(waf1/cip1) is essential for IL-4-mediated elevation of p27(kip1) and growth arrest of astrocytoma cells.
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Abbreviations
- AS:
-
antisense
- BrdU:
-
bromodeoxyuridine
- cdk:
-
cyclin-dependent kinase
- EGF:
-
epidermal growth factor
- FBS:
-
fetal bovine serum
- IL-4:
-
interleukin 4
- IP:
-
immunoprecipitation
- MS:
-
missense
- PBS:
-
phosphate-buffered saline
- pRb:
-
retinoblastoma protein
- RT–PCR:
-
reverse-transcribed polymerase chain reaction
- SDS:
-
sodium dodecyl sulfate
- STAT:
-
signal transducers and activators of transcription
- TGF-β:
-
transforming growth factor beta
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This work was supported by National Institutes of Health grant RO1NS-33932.
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Liu, J., Estes, M., Drazba, J. et al. Anti-sense oligonucleotide of p21(waf1/cip1) prevents Interleukin 4-mediated elevation of p27(kip1) in low grade astrocytoma cells. Oncogene 19, 661–669 (2000). https://doi.org/10.1038/sj.onc.1203373
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DOI: https://doi.org/10.1038/sj.onc.1203373
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