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J. Biol. Chem., Vol. 276, Issue 14, 11143-11150, April 6, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/14/11143    most recent M007073200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khanna, S. J. Articles by Dive, C. Search for Related Content PubMed PubMed Citation Articles by Khanna, S. J. Articles by Dive, C. Social Bookmarking                      What's this?

v-Abl Protein-tyrosine Kinase Up-regulates p21^WAF-1 in Cell Cycle Arrested and Proliferating Myeloid Cells^*

Sophia J. Khanna^§, Robin Brown^¶, Anthony D. Whetton, Kathryn L. Ball^**, and Caroline Dive

From the  Cancer Research Campaign Molecular Pharmacology Group, School of Biological Sciences, University of Manchester, G38 Stopford Building, Oxford Road, Manchester M13 9PT, ^¶ Glaxo Wellcome Research & Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertsfordshire SG1 2NY, the  Leukaemia Research Fund Cellular Development Unit, Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Sackville Street, Manchester M60 1QD, and the ^** Cancer Research Campaign Laboratory, Biomedical Research Centre, Ninewells Medical School, University of Dundee, Dundee DD1 95Y, United Kingdom

v-Abl protein-tyrosine kinase (PTK) promotes cell survival without cell proliferation in interleukin (IL)-3-deprived IC.DP premast cells (1). We now show that in these conditions v-Abl PTK transcriptionally up-regulated the cyclin-dependent kinase inhibitor (CDKI) p21^WAF-1 and inhibited CDK2 and CDK4. When readdition of IL-3 stimulated cell proliferation, p21^WAF-1 was inactivated as a CDKI despite maintenance of elevated protein level. p21^WAF-1 was also up-regulated yet was nonfunctional as a CDKI when v-Abl PTK was activated in cells maintained in IL-3, but this occurred without increased p21^WAF-1 transcription. Using a C-terminal epitope-specific p21^WAF-1 antibody, v-Abl PTK-mediated increase in p21^WAF-1 could be detected in intact cells only in the presence of IL-3. This indicated different binding partners of p21^WAF-1 and/or protein conformation in nondividing or proliferating cells, respectively. The binding of CDK2, CDK4, or proliferating cell nuclear antigen to p21^WAF-1 and its subcellular localization were unchanged in the presence or absence of IL-3. However, two-dimensional analysis revealed different forms of up-regulated p21^WAF-1 in IL-3-deprived, nondividing cells compared with IL-3-stimulated proliferating cells. These data demonstrate that elevation of the CDKI p21^WAF-1 is not always sufficient for cell cycle arrest and indicate an IL-3-sensitive pathway for the inactivation of p21^WAF-1 function as a CDKI.

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