PMID- 10558924
OWN - NLM
STAT- MEDLINE
DCOM- 19991208
LR  - 20161124
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 161
IP  - 1
DP  - 1999 Nov 15
TI  - Herbimycin A and geldanamycin inhibit okadaic acid-induced apoptosis and p38 
      activation in NRK-52E renal epithelial cells.
PG  - 59-74
AB  - It is important to understand the mechanisms by which phosphorylation-dependent 
      events play a role in regulation of apoptosis in toxicant-metabolizing organs 
      such as the kidney. Our previous work demonstrated that the toxicant and 
      phosphatase inhibitor okadaic acid induces apoptosis of renal epithelial cells 
      via a mechanism that appears to involve the modulation of c-raf-1, p38 kinase, 
      and extracellular regulatory kinase (ERK) cascades. Using the benzoquinone 
      ansamycins and tyrosine kinase inhibitors geldanamycin and herbimycin A, we 
      examined the contribution of tyrosine phosphorylation and c-raf-1 activities to 
      okadaic acid-induced apoptosis. In this report we show that both geldanamycin and 
      herbimycin A protected NRK-52E cells from okadaic acid-induced apoptosis, 
      abrogated the overall okadaic acid-induced kinase activation, and specifically 
      inhibited activation of p38 kinase by okadaic acid. Herbimycin A and geldanamycin 
      also abrogated okadaic-acid induced morphologic changes such as cell rounding and 
      cell membrane blebbing. Herbimycin A and geldanamycin caused pronounced cell 
      spreading, cell flattening, and a decrease in okadaic acid-induced loss of actin 
      filaments. Interestingly, herbimycin A showed more potent inhibitory effect than 
      geldanamycin, and herbimycin A alone inhibited okadaic acid-induced movement of 
      p38 kinase into the cytosol. These results imply that decreased p38 activity and 
      its cytosolic translocation together with cellular resistance to cytoskeletal 
      disorganization may play a significant role in resistance to 
      phosphorylation-dependent apoptosis. Furthermore, the results imply that changes 
      in cell shape may partially modulate the observed alterations in signal 
      transduction induced by okadaic acid.
CI  - Copyright 1999 Academic Press.
FAU - Davis, M A
AU  - Davis MA
AD  - Department of Pathology, University of Maryland School of Medicine, Baltimore, 
      Maryland, 21201, USA.
FAU - Carbott, D E
AU  - Carbott DE
LA  - eng
GR  - ES08157/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Actins)
RN  - 0 (Activating Transcription Factor 2)
RN  - 0 (Benzoquinones)
RN  - 0 (Chromatin)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Pyridines)
RN  - 0 (Quinones)
RN  - 0 (Transcription Factors)
RN  - 1W21G5Q4N2 (Okadaic Acid)
RN  - 1W306TDA6S (Rifabutin)
RN  - 70563-58-5 (herbimycin)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - Actins/metabolism
MH  - Activating Transcription Factor 2
MH  - Animals
MH  - Apoptosis/*drug effects/genetics
MH  - Benzoquinones
MH  - Cell Line
MH  - Cell Size/drug effects
MH  - Chromatin/drug effects/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Cytosol/drug effects/metabolism
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/cytology/drug effects/enzymology
MH  - Imidazoles/pharmacology
MH  - Kidney/cytology/*drug effects/enzymology
MH  - Lactams, Macrocyclic
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Okadaic Acid/*antagonists & inhibitors/*pharmacology/toxicity
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins c-raf/antagonists & inhibitors/metabolism
MH  - Pyridines/pharmacology
MH  - Quinones/*pharmacology
MH  - Rats
MH  - Rifabutin/pharmacology
MH  - Signal Transduction/drug effects
MH  - Transcription Factors/metabolism
MH  - Transfection
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 1999/11/24 00:00
MHDA- 1999/11/24 00:01
CRDT- 1999/11/24 00:00
PHST- 1999/11/24 00:00 [pubmed]
PHST- 1999/11/24 00:01 [medline]
PHST- 1999/11/24 00:00 [entrez]
AID - S0041-008X(99)98765-3 [pii]
AID - 10.1006/taap.1999.8765 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 1999 Nov 15;161(1):59-74. doi: 10.1006/taap.1999.8765.