Work

The Cyclin-Dependent Kinase Inhibitor p21CIP1/WAF1 Blocks Paclitaxel-Induced G2M Arrest and Attenuates Mitochondrial Injury and Apoptosis in p53-Null Human Leukemia Cells

Year: 2004

Type: article

Abstract: The functional significance of the cyclin-dependent kinase inhibitor (CDKI) p21(Cip1/WAF1) in paclitaxel-mediated lethality was examined in p53-null human leukemia cells (U937 and Jurkat). In these cells, paclitaxel exposure failed to induce p21(Cip1/Waf1) expression. Nevertheless, stable expression of U937 cells with a p21(Cip1/WAF1) antisense construct blocked paclitaxel-induced G(2)M arrest and increased mitochondrial injury, caspase activation, apoptosis, and loss of clonogenic potential. Consistent with these results, enforced expression of p21(Cip1/WAF1) in Jurkat cells increased the percentage of cells arrested in G2M and attenuated paclitaxel-mediated mitochondrial injury and apoptosis. Unexpectedly, enforced expression of p21(Cip1/WAF1) diminished paclitaxel-mediated inactivation of ERK, and reduced paclitaxel-induced activation of JNK as well as Bcl-2 phosphorylation. Together, these findings suggest that p21(Cip1/WAF1) partially protects p53-null human leukemia cells from paclitaxel-mediated lethality, and raise the possibility that p21(Cip1/WAF1)-associated perturbations in signal transduction pathways as well as Bcl-2 phosphorylation status may play a role in this phenomenon.

Source: Cell Cycle

DOI: 10.4161/cc.3.10.1161

Authors: Wesam Ahmed, Mohamed Rahmani, Paul Dent, Steven Grant

Institutions: Virginia Commonwealth University, Virginia Commonwealth University Medical Center

Language: English

Topic: Cancer-related Molecular Pathways

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: National Institutes of Health, National Cancer Institute