Association of BCL-2 with membrane hyperpolarization and radioresistance

Gilbert, Mark; Saad, Ali H.; Rupnow, Brent; Knox, Susan J.

doi:10.1002/(sici)1097-4652(199607)168:1<114::aid-jcp14>3.0.co;2-7

Cited by 38 publications

(11 citation statements)

References 24 publications

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“…A variety of biophysical mechanisms for transducing membrane voltage changes to secondary messenger effectors are now known (Cherubini et al, 2005;Levin et al, 2006;Murata et al, 2005). Our data suggest that control of regeneration by V-ATPase-dependent proton flux may take place through at least two mechanisms: control of cell number through modulation of membrane voltage (Cone, 1974;Cone and Cone, 1976;Gilbert et al, 1996;Olivotto et al, 1996;Tseng et al, 2007), and proper guidance of axon growth into the regenerate.…”

Section: Research Articlementioning

confidence: 77%

H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induceXenopustail regeneration

Adams¹,

Masi²,

Levin³

2007

Development

252

311

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In many systems, ion flows and long-term endogenous voltage gradients regulate patterning events, but molecular details remain mysterious. To establish a mechanistic link between biophysical events and regeneration, we investigated the role of ion transport during Xenopus tail regeneration. We show that activity of the V-ATPase H+ pump is required for regeneration but not wound healing or tail development. The V-ATPase is specifically upregulated in existing wound cells by 6 hours post-amputation. Pharmacological or molecular genetic loss of V-ATPase function and the consequent strong depolarization abrogates regeneration without inducing apoptosis. Uncut tails are normally mostly polarized, with discrete populations of depolarized cells throughout. After amputation, the normal regeneration bud is depolarized, but by 24 hours post-amputation becomes rapidly repolarized by the activity of the V-ATPase, and an island of depolarized cells appears just anterior to the regeneration bud. Tail buds in a non-regenerative `refractory' state instead remain highly depolarized relative to uncut or regenerating tails. Depolarization caused by V-ATPase loss-of-function results in a drastic reduction of cell proliferation in the bud, a profound mispatterning of neural components, and a failure to regenerate. Crucially, induction of H+ flux is sufficient to rescue axonal patterning and tail outgrowth in otherwise non-regenerative conditions. These data provide the first detailed mechanistic synthesis of bioelectrical,molecular and cell-biological events underlying the regeneration of a complex vertebrate structure that includes spinal cord, and suggest a model of the biophysical and molecular steps underlying tail regeneration. Control of H+ flows represents a very important new modality that, together with traditional biochemical approaches, may eventually allow augmentation of regeneration for therapeutic applications.

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Section: Research Articlementioning

confidence: 77%

H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induceXenopustail regeneration

Adams¹,

Masi²,

Levin³

2007

Development

252

311

View full text Add to dashboard Cite

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“…Accordingly, long-term clonogenic assays also demonstrated that only Bcl-x L provided protection for DU-145 cells (Figure 6, panel c). Multiple reports confirm that prevention from apoptosis by Bcl-2 following DNA damage does not guarantee enhanced long-term tumor cell survival (Sentman et al, 1991;Collins et al, 1992;Strasser et al, 1994;Gilbert et al, 1996;Lock and Stribinskiene, 1996;Kyprianou et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 and Bcl-xL differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24

et al. 2003

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“…For example, up-regulation of the antiapoptotic Bcl-2 family members in certain tumors has been implicated in their chemo-and radioresistance. 10,11 Chondrosarcoma and other sarcomas are known to express genes that regulate both cell death and cell survival. 12 Therefore, down-regulating antiapoptotic genes may be one logical approach in enhancing the efficacy of radiation and chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Targeting of cell survival genes using small interfering RNAs (siRNAs) enhances radiosensitivity of Grade II chondrosarcoma cells

Kim

Seo

Cho

et al. 2007

Journal Orthopaedic Research

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ABSTRACT:The main treatment for chondrosarcoma is surgical resection with a wide margin. However, there are certain chondrosarcomas, such as those found in the pelvis and the spine, which cannot be resected adequately with surgery alone. Unfortunately, most chondrosarcomas are resistant to radiation and chemotherapy. Radiation and chemotherapy are thought to kill chondrosarcoma cells by inducing apoptosis, or programmed cell death. In this article, we hypothesize that antiapoptotic gene silencing enhances radiosensitivity in chondrosarcoma cells by facilitating apoptotic pathways. We knocked down antiapoptotic genes in chondrosarcoma cells using small interfering RNAs (siRNAs). Two well-established Grade II human chondrosarcoma cell lines were pretreated with siRNAs that specifically target mRNAs for Bcl-2, Bcl-xL, or XIAP. The cells were then treated with radiation. Cell death was assessed by flow cytometry. Cell survival and proliferation were measured by clonogenic survival assays. Chondrosarcoma cells exhibited radioresistance and increased the expression of Bcl-2, Bcl-xL, and XIAP in response to radiation. When one of the Bcl-2, Bcl-xL, or XIAP genes was silenced with the corresponding siRNA, radiosensitivity increased up to 9.2-fold (p < 0.05). When two out of the three antiapoptotic mRNAs were knocked down simultaneously, there was an 11.3-fold increase in cell death after radiation (p < 0.05). Our findings support a novel therapeutic concept that gene silencing may be used as a molecular adjuvant therapy for radioresistant sarcomas. ß

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Association of BCL-2 with membrane hyperpolarization and radioresistance

Cited by 38 publications

References 24 publications

H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induceXenopustail regeneration

H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induceXenopustail regeneration

Bcl-2 and Bcl-xL differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24

Targeting of cell survival genes using small interfering RNAs (siRNAs) enhances radiosensitivity of Grade II chondrosarcoma cells

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