Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells

Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells

Bibliographic Details
Main Author: Bhanot, Haymanti
Language:English
Published: University of Toledo Health Science Campus / OhioLINK 2011
Subjects:
Biology
Cellular Biology
Molecular Biology
Ras
methuosis
glioblastoma
Arf6
Rac1
R-Ras
cell death
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=mco1315945810
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-mco13159458102021-08-03T05:38:54Z Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells Bhanot, Haymanti Biology Cellular Biology Molecular Biology Ras methuosis glioblastoma Arf6 Rac1 R-Ras cell death Methuosis is a unique form of non-apoptotic cell death that is characterized by dysfunction in the trafficking of clathrin-independent endosomes. This leads to extensive cellular vacuolization and ultimately death of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively activated H-Ras. This study identifies the signaling pathways that govern H-Ras-induced methuosis in human glioblastoma cells. Our studies establish that the small GTPases, Rac1 and Arf6, and the Arf6 GAP, GIT1, act as key downstream components of the signaling pathway underlying H-Ras-induced methuosis. Activated H-Ras-induced methuosis depends upon Rac1 activation and the consequent interaction of active Rac1 with GIT1 to inactivate Arf6 and prevent the recycling of the clathrin-independent endosomes back to the plasma membrane. Studies to test the effect of a closely related Ras GTPase, R-Ras, in glioblastoma cells reveal that it induces cellular vacuolation but does not lead to cell death. Expression of constitutively active R-Ras in glioblastoma cells induces cytoplasmic vacuolation dependent upon Rac1 activation and subsequent inactivation of Arf6. The latter might prevent recycling of vacuoles back to the plasma membrane. However, R-Ras-induced vacuoles do not expand progressively like H-Ras-induced vacuoles, and the cells do not undergo methuosis. H-Ras(G12V) expression in the cells leads to an increase in the levels of active Rab7. Vacuoles in cells expressing H-Ras(G12V) contain H-Ras(G12V) and Rab7(Q67L) on their membranes. These vacuoles fail to fuse with lysosomes. Interestingly, R-Ras(G38V) does not localize to vacuoles. Unlike the cells expressing H-Ras(G12V), cells expressing R-Ras(G38V) are not metabolically compromised. We postulate that though the expression of active R-Ras in glioblastoma cells induces cellular vacuolation, the induced vacuoles might be competent to fuse with the lysosomes, thus preventing methuosis. Further studies to identify the different signaling pathways underlying the effects of H-Ras and R-Ras on vesicular trafficking would help to identify key regulators of the initial steps that lead to methuosis. This might help identify potential therapeutic targets that can be manipulated to induce methuosis in cancers that are refractory to apoptosis. 2011-12-29 English text University of Toledo Health Science Campus / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=mco1315945810 http://rave.ohiolink.edu/etdc/view?acc_num=mco1315945810 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biology
Cellular Biology
Molecular Biology
Ras
methuosis
glioblastoma
Arf6
Rac1
R-Ras
cell death
spellingShingle Biology
Cellular Biology
Molecular Biology
Ras
methuosis
glioblastoma
Arf6
Rac1
R-Ras
cell death
Bhanot, Haymanti
Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells
author Bhanot, Haymanti
author_facet Bhanot, Haymanti
author_sort Bhanot, Haymanti
title Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells
title_short Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells
title_full Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells
title_fullStr Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells
title_full_unstemmed Mechanisms Underlying Ras-Induced Methuosis in Human Glioblastoma Cells
title_sort mechanisms underlying ras-induced methuosis in human glioblastoma cells
publisher University of Toledo Health Science Campus / OhioLINK
publishDate 2011
url http://rave.ohiolink.edu/etdc/view?acc_num=mco1315945810
work_keys_str_mv AT bhanothaymanti mechanismsunderlyingrasinducedmethuosisinhumanglioblastomacells
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