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p38 mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during Chemotherapeutic Drug-induced mitotic arrest

By Karl Deacon, Pratibha Mistry, Jonathan Chernoff, Jonathan L. Blank and Rajnikant Patel


Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death.Peer-reviewedPublisher Versio

Publisher: American Society for Cell Biology
Year: 2003
DOI identifier: 10.1091/mbc.E02-10-0653
OAI identifier:

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  3. (2001). Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. doi
  4. (1997). Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase. doi
  5. (2000). BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. doi
  6. (1998). Bax directly induces release of cytochrome c from isolated mitochondria. doi
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  8. (1996). BAX-induced cell death may not require interleukin IL-converting enzyme-like proteases. doi
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  10. (1999). Bid-induced conformational change of Bax is responsible for mitochondrail cytochrome c release during apoptosis. doi
  11. (1999). Calcium/calmodulin-dependent phosphorylation and activation of human cdc25-C at the G2/M phase transition in HeLa cells. doi
  12. (1995). Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. doi
  13. (1997). Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, doi
  14. (2000). Complexity in the spindle checkpoint. doi
  15. (1999). Conformation of the Bax C-terminus regulates subcellular location and cell death. doi
  16. (2003). Control of mitotic transitions by the anaphase-promoting complex.
  17. (1997). Coupling cell division and cell death to microtubule dynamics. doi
  18. (1997). Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. doi
  19. (1999). Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells. doi
  20. (1999). How BAD phosphorylation is good for survival.
  21. (1996). Identification of a human mitotic checkpoint gene: hsMAD2. doi
  22. (1999). Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. doi
  23. (1995). Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. doi
  24. (2001). Inhibition of extracellular signal-regulated kinase (ERK) mediates cell cycle phase independent apoptosis in vinblastine-treated ML-1 cells.
  25. (2000). Inhibition of HER2/Neu (erbB-2) and mitogen-activated protein kinases enhance tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells.
  26. (2000). Insulin-like growth factor-1 protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor -induced mitogen-activated protein kinase and nuclear factor B signaling pathways. doi
  27. (2001). Involvement of p38 in apoptosis-associated membrane blebbing and nuclear condensation. doi
  28. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. doi
  29. (1999). MEK kinase 1 (MEKK1) transduces c-Jun NH2-terminal kinase activation in response to changes in the microtubule cytoskeleton. doi
  30. (1999). MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. doi
  31. (1997). Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. doi
  32. (1995). Microtubule dynamics: taking aim at a moving target. doi
  33. (1998). Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both ras and apoptosis signal-regulating kinase pathways. doi
  34. (2000). Microtubule-interfering agents stimulate the transcription of cyclo-oxygenase-2. Evidence for involvement of ERK1/2 and p38 mitogen-activated protein kinase pathways. doi
  35. (1996). Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death.
  36. (1997). Movement of bax from the cytosol to mitochondria during apoptosis. doi
  37. (1995). Opposing effects of ERK and JNK-p38 MAPKs on apoptosis. doi
  38. (2000). P21-activated kinase 1 phosphorylares the death agonist Bad and protects cells from apoptosis. doi
  39. (2001). p21-activated protein kinase -PAK suppresses programmed cell death of BALB3T3 fibroblasts. doi
  40. (1998). p21WAF1 is dynamically associated with JNK in human T-lymphocytes during cell cycle progression.
  41. (2000). p38 MAPK mediates Bax translocation in nitric oxide-induced apoptosis in neurons. doi
  42. (2000). p38 Mitogenactivated protein kinase pathway protects adult rat ventricular myocytes against -adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation. doi
  43. (2001). Paclitaxel induces prolonged activation of the Ras/MEK/ERK pathway independently of activating the programmed cell death machinery. doi
  44. (2000). Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. doi
  45. (1999). PAK to the future. doi
  46. (1996). Requirement for ceramide-initiated SAPK/ JNK signaling in stress-induced apoptosis. doi
  47. (1999). Role of p38-mitogen-activated protein kinase in spontaneous apoptosis of human neutrophils.
  48. (2001). Selective potentiation of paclitaxel (taxol)-induced cell death by mitogen-activated protein kinase kinase inhibition in human cell lines.
  49. (1995). Taxol-induced mitotic block triggers rapid onset of a p53-independent apoptotic pathway.
  50. (2000). The Akt proto-oncogene links Ras to Pak and cell survival signals. doi
  51. (1991). The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapy. doi
  52. (1997). The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. doi
  53. (2000). The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. doi
  54. (2001). The role of erk1/2 and p38 MAP-kinase pathways in taxolinduced apoptosis in human ovarian carcinoma cells. doi
  55. (2001). The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis. doi
  56. (2001). The ups and downs of MEK kinase interactions. doi
  57. (2000). Waiting for anaphase: Mad2 and the spindle assembly checkpoint.

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