Dataset Information

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.

ABSTRACT: Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD(+) binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation.

SUBMITTER: Nicholls C

PROVIDER: S-EPMC3421169 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.

Nicholls Craig C Pinto Alexander Ruvantha AR Pinto Alexander Ruvantha AR Li He H Li Ling L Wang Lihui L Simpson Richard R Liu Jun-Ping JP

Proceedings of the National Academy of Sciences of the United States of America 20120730 33

Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD(+) binding region on GAPDH is re ...[more]

PMID: 22847419

Similar Datasets

Project description:Glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that also mediates cell death under oxidative stress. We reported previously that the active-site cysteine (Cys-152) of GAPDH plays an essential role in oxidative stress-induced aggregation of GAPDH associated with cell death, and a C152A-GAPDH mutant rescues nitric oxide (NO)-induced cell death by interfering with the aggregation of wild type (WT)-GAPDH. However, the detailed mechanism underlying GAPDH aggregate-induced cell death remains elusive. Here we report that NO-induced GAPDH aggregation specifically causes mitochondrial dysfunction. First, we observed a correlation between NO-induced GAPDH aggregation and mitochondrial dysfunction, when GAPDH aggregation occurred at mitochondria in SH-SY5Y cells. In isolated mitochondria, aggregates of WT-GAPDH directly induced mitochondrial swelling and depolarization, whereas mixtures containing aggregates of C152A-GAPDH reduced mitochondrial dysfunction. Additionally, treatment with cyclosporin A improved WT-GAPDH aggregate-induced swelling and depolarization. In doxycycline-inducible SH-SY5Y cells, overexpression of WT-GAPDH augmented NO-induced mitochondrial dysfunction and increased mitochondrial GAPDH aggregation, whereas induced overexpression of C152A-GAPDH significantly suppressed mitochondrial impairment. Further, NO-induced cytochrome c release into the cytosol and nuclear translocation of apoptosis-inducing factor from mitochondria were both augmented in cells overexpressing WT-GAPDH but ameliorated in C152A-GAPDH-overexpressing cells. Interestingly, GAPDH aggregates induced necrotic cell death via a permeability transition pore (PTP) opening. The expression of either WT- or C152A-GAPDH did not affect other cell death pathways associated with protein aggregation, such as proteasome inhibition, gene expression induced by endoplasmic reticulum stress, or autophagy. Collectively, these results suggest that NO-induced GAPDH aggregation specifically induces mitochondrial dysfunction via PTP opening, leading to cell death.

Dataset Information

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.

Publications

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets