Inhibition of ICMT induces endothelial cell apoptosis through GRP94.

Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Research Abstract Details 

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Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Abstract Text:

Qing Lu,Elizabeth O Harrington,Julie Newton,Matthew Jankowich,Sharon Rounds,

Isoprenylcysteine-O-carboxyl methyltransferase (ICMT) catalyzes methylation of proteins containing a C-terminal CAAX motif. We have previously shown that chemical inhibition of ICMT caused endothelial cell apoptosis, an effect correlated with decreased Ras and RhoA carboxyl methylation and GTPase activities. In the current study, proteomic analysis of pulmonary artery endothelial cells (PAEC) exposed to the ICMT inhibitor, N-acetyl-geranylgeranyl-cysteine (AGGC), demonstrated a shift in the isoelectric points (pI) of the glucose-regulated protein (GRP) 94. Two-dimensional PAGE and immunoblot analysis further documented that ICMT inhibition caused multiple changes in the pI of GRP94. GRP94 is an endoplasmic reticulum molecular chaperone, a component of the unfolded protein response (UPR), and is involved in apoptosis. Immunofluorescence analyses revealed redistribution and aggregation of GRP94 after 3 h exposure to AGGC. A similar finding was noted with calnexin. In addition, GRP94 protein levels were significantly diminished upon 18 h AGGC exposure or ICMT suppression. The effects of ICMT inhibition on changes in GRP94 subcellular localization and protein content were blunted by overexpression of constitutively active RhoA or a caspase inhibitor. Furthermore, GRP94 depletion augmented endothelial cell apoptosis induced by ICMT inhibition. These results indicate that ICMT inhibition leads to GRP94 relocalization, aggregation, and degradation; effects were dependent upon the activities of RhoA and caspases. We speculate that changes in the pI, subcellular localization, and protein level of GRP94 cause endothelial cell apoptosis, possibly through UPR dysfunction. These studies suggest a novel link between RhoA GTPases and the UPR.

Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Publishing Authors By Initials

Q Lu,EO Harrington,J Newton,M Jankowich,S Rounds,

For similar enzymes and coenzymes: enzymes: hydrolases: acid anhydride hydrolases: gtp phosphohydrolases: gtp-binding proteins: monomeric gtp-binding proteins: rho gtp-binding proteins: rhoa gtp-binding protein research abstracts see: enzymes and coenzymes: enzymes: hydrolases: acid anhydride hydrolases: gtp phosphohydrolases: gtp-binding proteins: monomeric gtp-binding proteins: rho gtp-binding proteins: rhoa gtp-binding protein research

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Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: American journal of respiratory cell and molecular

VOLUME: 37

Page Numbers: 20-30

Journal Abbreviation: Am. J. Respir. Cell Mol. Biol.

ISSN: 1044-1549

DAY: 8

MONTH: 03

YEAR: 2007

Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8917225

Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Keywords Mesh Terms:

KEYWORDS: rhoA GTP-Binding Protein

MESH TERMS: metabolism

Chemical & Substance for Abstract: Inhibition of ICMT induces endothelial cell apoptosis through GRP94. Information

Substance Name: rhoA GTP-Binding Protein

Registry Number: EC 3.6.5.2

Grant and Affiliation Information for Inhibition of ICMT induces endothelial cell apoptosis through GRP94.

AFFILIATION: Providence VA Medical Center, Pulmonary/Critical Care Medicine Section, 830 Chalkstone Avenue, Providence, RI 02908, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL 67795

ACRONYM: HL

MEDLINETA: Am J Respir Cell Mol Biol

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