Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells

M. V. Blagosklonny, Y. Chuman, Raymond Bergan, T. Fojo

Research output: Contribution to journalArticle

77 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1028-1036
Number of pages9
JournalLeukemia
Volume13
Issue number7
StatePublished - 1999
Externally publishedYes

Fingerprint

Mitogen-Activated Protein Kinases
Microtubules
Leukemia
Phosphorylation
Apoptosis
Paclitaxel
Pharmaceutical Preparations
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Jurkat Cells
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Phorbol Esters
p38 Mitogen-Activated Protein Kinases
Growth
Protein-Tyrosine Kinases
Proteins

Keywords

  • Apoptosis
  • Bcl-2
  • Leukemia
  • MAPK
  • Paclitaxel
  • Raf-1

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells. / Blagosklonny, M. V.; Chuman, Y.; Bergan, Raymond; Fojo, T.

In: Leukemia, Vol. 13, No. 7, 1999, p. 1028-1036.

Research output: Contribution to journalArticle

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