Abstract
Raf-1 activation and Bcl-2 hyperphosphorylation following treatment with paclitaxel (Taxol) or other microtubule-active drugs is associated with mitotic arrest. Here we show that microtubule-active drugs do not activate the mitogen-activated protein kinase (MAPK) pathway in leukemia cells. PD98059, a MEK inhibitor, and SB202190, a p38 MAP kinase inhibitor, do not abrogate Bcl-2 phosphorylation nor apoptosis. Simultaneously with PARP cleavage, paclitaxel induces cleavage of Bcl-2 protein yielding a potentially pro-apoptotic 22 kDa product. In comparison, the stimulation of Raf-1 by phorbol ester (TPA) activates the MAPK pathway, causes MAPK-dependent p21(WAF1/CIP1) induction, Rb dephosphorylation and growth arrest without Bcl-2 phosphorylation or apoptosis. Like TPA, cAMP induces p21(WAF1/CIP1) but does not cause Bcl-2 phosphorylation. MEKK1 and as, upstream activators of JNK and ERK MAPK, also fail to induce Bcl-2 hyperphosphorylation. Although Lck tyrosine kinase has been recently implicated in Raf-1 activation during mitotic arrest, microtubule-active drugs induce Raf-1/Bcl-2 hyperphosphorylation and apoptosis in a Lck-deficient Jurkat cells. Therefore, microtubule-active drugs induce apoptosis which is associated with Raf-1 and Bcl-2 phosphorylation and Bcl-2 cleavage but is independent of the MAPK pathway. In contrast, TPA-activated MAPK pathway causes p21(WAF1/CIPC1)-dependent growth arrest without apoptosis.
Original language | English (US) |
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Pages (from-to) | 1028-1036 |
Number of pages | 9 |
Journal | Leukemia |
Volume | 13 |
Issue number | 7 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
Keywords
- Apoptosis
- Bcl-2
- Leukemia
- MAPK
- Paclitaxel
- Raf-1
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research