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GAS1 induces cell death through an intrinsic apoptotic pathway

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Abstract

Growth Arrest Specific 1 (GAS1) is a protein expressed when cells are arrested and during development. When ectopically expressed, GAS1 induces cell arrest and apoptosis of different cell lines, and we have previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity inhibiting the GDNF-mediated intracellular survival signaling. In the present work, we have dissected the molecular pathway leading to cell death. We employed the SH-SY5Y human neuroblastoma cell line that expresses GAS1 when deprived of serum. We observed, as we have previously described, that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT. We have now determined that the presence of GAS1 also triggers the dephosphorylation of BAD, which, in turn, provokes the release of Cytochrome-c from the mitochondria to the cytosol activating caspase-9, prompting the activity of caspase-3 and resulting in apoptosis of the cells. The apoptotic process is intrinsic, because there is no activation of caspase-8, thus this is consistent with apoptosis induced by the lack of trophic support. Interestingly, in cells where GAS1 has been silenced there is a significant delay in the onset of apoptosis.

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Acknowledgments

We want to thank Victor H. Rosales for his assistance with the flow cytometry assays, and Dr. J.M. Hernández (Cinvestav) for the kind gift of the antibody against β-ACTIN, and Dr. B. Vogelstein (Johns Hopkins University) for providing us with the pAdTrack-CMV plasmid. This work was partially supported by Conacyt (Mexico) Grant 127357 (J.S).

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Authors and Affiliations

  1. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Av. Instituto Politécnico Nacional # 2508, 07300, Mexico, D.F, Mexico

    Natanael Zarco & José Segovia

  2. Departamento de Biología Molecular e Histocompatibilidad, Hospital General Dr. Manuel Gea González, Mexico, D.F, Mexico

    Ricardo González-Ramírez

  3. Departamento de Matemáticas, Universidad Autónoma Metropolitana-Iztapalapa, Mexico, D.F, Mexico

    Rosa O. González

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  1. Natanael Zarco
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  2. Ricardo González-Ramírez
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  3. Rosa O. González
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  4. José Segovia
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Correspondence to José Segovia.

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Zarco, N., González-Ramírez, R., González, R.O. et al. GAS1 induces cell death through an intrinsic apoptotic pathway. Apoptosis 17, 627–635 (2012). https://doi.org/10.1007/s10495-011-0696-8

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