PMID- 12956705
OWN - NLM
STAT- MEDLINE
DCOM- 20031023
LR  - 20190815
IS  - 0953-816X (Print)
IS  - 0953-816X (Linking)
VI  - 18
IP  - 5
DP  - 2003 Sep
TI  - Tissue inhibitor of metalloproteinases-3 and matrix metalloproteinase-3 regulate 
      neuronal sensitivity to doxorubicin-induced apoptosis.
PG  - 1050-60
AB  - Metalloproteinase activity at the cell surface influences cellular sensitivity to 
      extrinsic death vs. survival signals in a variety of cell types, through 
      proteolytic shedding of cell surface signalling molecules. Tissue inhibitor of 
      metalloproteinases-3 (TIMP-3) is a unique natural metalloproteinase inhibitor 
      that plays a pro-apoptotic role through its ability to inhibit metalloproteinases 
      that proteolytically cleave death receptors and their ligands from the cell 
      surface. To study the convergence of metalloproteinase activity and death 
      receptor signalling in neurons, we established an in vitro model of neuronal 
      apoptosis utilizing the chemotherapeutic drug, doxorubicin (Dox). Primary 
      cultures established from embryonic rat cerebral cortices displayed robust and 
      selective neuronal apoptosis in response to Dox, an effect that was dependent on 
      the activation of the death receptor, Fas. We demonstrate that both TIMP-3 and 
      matrix metalloproteinase-3 (MMP-3) are constitutively expressed by primary 
      cortical neurons in culture, and selectively modulated Fas-mediated neuronal 
      apoptosis induced by Dox. Metalloproteinase inhibition by TIMP-3 was found to be 
      necessary for Dox-induced neuronal death, whereas addition of active MMP-3 
      markedly attenuated apoptosis and diminished Fas-Fas ligand interaction at the 
      cell surface. These observations implicate a physiological role for the balance 
      of TIMP-3 and MMP-3 activity at the neuronal surface in regulating death receptor 
      sensitivity. The convergence of metalloproteinase activity and death receptor 
      signalling at the cell surface may influence neuronal cell death vs. survival 
      decisions.
FAU - Wetzel, M
AU  - Wetzel M
AD  - Department of Neurosciences, University of New Mexico School of Medicine, Health 
      Sciences Center, Albuquerque, NM 87131, USA.
FAU - Rosenberg, G A
AU  - Rosenberg GA
FAU - Cunningham, L A
AU  - Cunningham LA
LA  - eng
GR  - NS21169/NS/NINDS NIH HHS/United States
GR  - NS38655/NS/NINDS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - France
TA  - Eur J Neurosci
JT  - The European journal of neuroscience
JID - 8918110
RN  - 0 (Antigens, CD)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Indoles)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Thiophenes)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
RN  - 0 (fas Receptor)
RN  - 47165-04-8 (DAPI)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - 80168379AG (Doxorubicin)
RN  - BK349F52C9 (batimastat)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 4.2.1.11 (Phosphopyruvate Hydratase)
SB  - IM
MH  - Animals
MH  - Antigens, CD/metabolism
MH  - Antineoplastic Agents/*pharmacology
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Cell Count
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/metabolism
MH  - Doxorubicin/*pharmacology
MH  - Embryo, Mammalian
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Immunoglobulin G/pharmacology
MH  - Immunohistochemistry
MH  - Indoles/metabolism
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Matrix Metalloproteinase 3/immunology/*metabolism
MH  - Neurons/*drug effects/physiology
MH  - Phenylalanine/*analogs & derivatives/pharmacology
MH  - Phosphopyruvate Hydratase/metabolism
MH  - Precipitin Tests/methods
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Inbred WKY
MH  - Receptors, Tumor Necrosis Factor/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I
MH  - Reverse Transcriptase Polymerase Chain Reaction/methods
MH  - Thiophenes/pharmacology
MH  - Time Factors
MH  - Tissue Inhibitor of Metalloproteinase-3/*metabolism
MH  - fas Receptor/pharmacology
EDAT- 2003/09/06 05:00
MHDA- 2003/10/24 05:00
CRDT- 2003/09/06 05:00
PHST- 2003/09/06 05:00 [pubmed]
PHST- 2003/10/24 05:00 [medline]
PHST- 2003/09/06 05:00 [entrez]
AID - 2838 [pii]
AID - 10.1046/j.1460-9568.2003.02838.x [doi]
PST - ppublish
SO  - Eur J Neurosci. 2003 Sep;18(5):1050-60. doi: 10.1046/j.1460-9568.2003.02838.x.