| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205; and 2Department of Internal Medicine and Therapeutics, Osaka University, Graduate School of Medicine, Osaka 545, Japan
Submitted 1 April 2004 ; accepted in final form 12 May 2004
Cisplatin treatment induces extensive death of the proximal tubules in mice. We also demonstrated that treatment of immortalized mouse proximal tubule cells (TKPTS) with 25 µM cisplatin induces apoptotic death in vitro. Here, we demonstrate that members of the MAPKs such as ERK, JNK, and p38 are all activated after cisplatin treatment both in vivo and in vitro. Because MAPKs mediate cell survival and death, we studied their role in cisplatin-induced cell death in vitro. Apoptosis was confirmed by cell morphology, fluorescence-activated cell-sorting analysis, annexin V/propidium iodide binding, and caspase-3 activation in TKPTS cells. Inhibition of ERK, but not JNK or p38, abolished caspase-3 activation and apoptotic death, suggesting a prodeath role of ERK in cisplatin-induced injury. We also determined that cisplatin-induced ERK as well as caspase-3 activation are epidermal growth factor receptor (EGFR) and c-src dependent because inhibition of these genes inhibited ERK and caspase-3 activation and attenuated apoptotic death. These results suggest that caspase-3 mediates cisplatin-induced cell death in TKPTS cells via an EGFR/src/ERK-dependent pathway. We also suggest that the prodeath effect of ERK is injury type dependent because during oxidant injury, ERK supports survival rather than death in the same cells. We propose that injury-specific outcome diverges downstream from ERK in cisplatin- or H2O2-mediated cell survival and death.
apoptosis; mitogen-activating protein kinase; epidermal growth factor receptor; c-src
This article has been cited by other articles:
|
|
 |
|
  J. C. Puigvert, S. Huveneers, L. Fredriksson, M. o. h. Veld, B. van de Water, and E. H. J. Danen Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity Mol. Pharmacol., April 1, 2009; 75(4): 947 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jiang and Z. Dong Regulation and Pathological Role of p53 in Cisplatin Nephrotoxicity J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 300 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Sanz, B. Santamaria, M. Ruiz-Ortega, J. Egido, and A. Ortiz Mechanisms of Renal Apoptosis in Health and Disease J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1634 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Arany, J. Herbert, Z. Herbert, and R. L. Safirstein Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells Am J Physiol Renal Physiol, March 1, 2008; 294(3): F577 - F581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lechner, N. A. Malloth, P. Jennings, D. Heckl, W. Pfaller, and T. Seppi Opposing roles of EGF in IFN-{alpha}-induced epithelial barrier destabilization and tissue repair Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1843 - C1850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wei, G. Dong, T. Yang, J. Megyesi, P. M. Price, and Z. Dong Activation and involvement of p53 in cisplatin-induced nephrotoxicity Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1282 - F1291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kersting, C. Gebert, K. Agelopoulos, H. Schmidt, P. J. van Diest, H. Juergens, W. Winkelmann, M. Kevric, G. Gosheger, B. Brandt, et al. Epidermal Growth Factor Receptor Expression in High-Grade Osteosarcomas Is Associated with a Good Clinical Outcome Clin. Cancer Res., May 15, 2007; 13(10): 2998 - 3005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ramesh, S. R. Kimball, L. S. Jefferson, and W. B. Reeves Endotoxin and cisplatin synergistically stimulate TNF-{alpha} production by renal epithelial cells Am J Physiol Renal Physiol, February 1, 2007; 292(2): F812 - F819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhuang, Y. Yan, R. A. Daubert, J. Han, and R. G. Schnellmann ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells Am J Physiol Renal Physiol, January 1, 2007; 292(1): F440 - F447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, N. Pabla, C.-Y. Wang, W. Wang, P. V. Schoenlein, and Z. Dong Caspase-mediated cleavage of ATM during cisplatin-induced tubular cell apoptosis: inactivation of its kinase activity toward p53 Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1300 - F1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Nowak, G. L. Clifton, M. L. Godwin, and D. Bakajsova Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells Am J Physiol Renal Physiol, October 1, 2006; 291(4): F840 - F855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ramesh and W. B. Reeves p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice Am J Physiol Renal Physiol, July 1, 2005; 289(1): F166 - F174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kim, Y. Yan, R. L. Kortum, S. M. Stoeger, M. K. Sgagias, K. Lee, R. E. Lewis, and K. H. Cowan Expression of Kinase Suppressor of Ras1 Enhances Cisplatin-Induced Extracellular Signal-Regulated Kinase Activation and Cisplatin Sensitivity Cancer Res., May 15, 2005; 65(10): 3986 - 3992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. J. Wu, L. L. Muldoon, and E. A. Neuwelt The Chemoprotective Agent N-Acetylcysteine Blocks Cisplatin-Induced Apoptosis through Caspase Signaling Pathway J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 424 - 431. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
