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Anti-sense oligonucleotide of p21(waf1/cip1) prevents Interleukin 4-mediated elevation of p27(kip1) in low grade astrocytoma cells

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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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Acknowledgements

This work was supported by National Institutes of Health grant RO1NS-33932.

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Authors and Affiliations

  1. Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, 44109, Ohio, OH, USA

    Jinbo Liu, Melinda L Estes, Haiyan Liu, Barbara S Jacobs & Barbara P Barna

  2. The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Judith A Drazba

  3. Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Richard Prayson

  4. Department of Neurological Surgery, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Seiji Kondo & Gene H Barnett

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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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