GAS1 induces cell death through an intrinsic apoptotic pathway

Zarco, Natanael; González‐Ramírez, Ricardo; González, Rosa O.; Segovia, José

doi:10.1007/s10495-011-0696-8

Cited by 45 publications

(42 citation statements)

References 36 publications

(32 reference statements)

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“…It is interesting that the effects of GAS1 in inducing apoptosis are independent of the SHH pathway (DominguezMonzon et al 2009;Dominguez-Monzon et al 2011;Zarco et al 2012). Previous experiments have shown that the overexpression of GAS1 can potentiate SHH signaling and that GAS1 inactivation decreases SHH signaling in the neural tube (Tenzen et al 2006;Allen, Tenzen, and McMahon 2007;Martinelli and Fan 2007;Allen et al 2011;Izzi et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Growth Arrest Specific 1 (GAS1) Is Abundantly Expressed in the Adult Mouse Central Nervous System

Zarco

Bautista

Cuéllar

et al. 2013

J Histochem Cytochem.

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Growth arrest specific 1 (GAS1) is a pleiotropic protein that induces apoptosis and cell arrest in different tumors, but it is also involved in the development of the nervous system and other tissues and organs. This dual ability is likely caused by its capacity to interact both by inhibiting the intracellular signaling cascade induced by glial cell-line derived neurotrophic factor and by facilitating the activity of the sonic hedgehog pathway. The presence of GAS1 mRNA has been described in adult mouse brain, and here we corroborated this observation. We then proceeded to determine the distribution of the protein in the adult central nervous system (CNS). We detected, by western blot analysis, expression of GAS1 in olfactory bulb, caudate-putamen, cerebral cortex, hippocampus, mesencephalon, medulla oblongata, cerebellum, and cervical spinal cord. To more carefully map the expression of GAS1, we performed double-label immunohistochemistry and noticed expression of GAS1 in neurons in all brain areas examined. We also observed expression of GAS1 in astroglial cells, albeit the pattern of expression was more restricted than that seen in neurons. Briefly, in the present article, we report the widespread distribution and cellular localization of the GAS1 native protein in adult mammalian CNS.

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Section: Discussionmentioning

confidence: 99%

Growth Arrest Specific 1 (GAS1) Is Abundantly Expressed in the Adult Mouse Central Nervous System

Zarco

Bautista

Cuéllar

et al. 2013

J Histochem Cytochem.

Self Cite

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“…[89,96,[102][103][104] Ptc and Gli are highly expressed in gliomas and are considered oncogenes. [105,106] Therefore this would suggest that Gas1 could enhance the effect of Shh, inducing the proliferation of glioma and neuroblastoma cells, however we showed that Gas1 inhibits cell proliferation of glioma cells even in the presence of the Shh molecular machinery, [107,108] which suggest that in tumors Gas1 inhibits the GDNF signaling pathway.…”

Section: Gas1 Promotes Shh Signalingmentioning

confidence: 81%

“…[114] In neuroblastoma and glioma cells, Gas1 blocks cell cycle progression, inhibits proliferation and induces cell death by inhibiting the GDNF/AKT pathway. [107,108,115,116] We showed that Gas1 prevents the phosphorylation of Ret Tyr1062 and reduces the activation of AKT [ Figure 1]. This leads to the translocation of BAD to the mitochondria and the release of cytochrome-C to the cytosol which in turn induces the activation of Caspases 9 and 3.…”

Section: Gas1 Inhibits the Signaling Induced By Gdnf And Arteminmentioning

confidence: 99%

“…This leads to the translocation of BAD to the mitochondria and the release of cytochrome-C to the cytosol which in turn induces the activation of Caspases 9 and 3. [107,108,[115][116][117][118] Recently Wang and et al [100] demonstrated that Gas1 promotes excitotoxicity in dopaminergic neurons by inhibiting the GDNF signaling pathway.…”

Section: Gas1 Inhibits the Signaling Induced By Gdnf And Arteminmentioning

confidence: 99%

“…[107,108,[115][116][117][118]124,125] It is worth noting that the downregulation of GAS1 is associated with the progression of thyroid and prostate cancer and with a poor prognosis of survival. [126,127] Additionally the loss of GAS1 increases the metastasis of breast, prostate and gastric cancers.…”

Section: Potential Therapeutic Effect Of Gas1 For the Treatment Of Glmentioning

confidence: 99%

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Effects of Gas1 on gliomas: a review on current preclinical studies

Segovia¹,

Bautista²,

Lara-Lozano³

2016

JCMT

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Glioblastoma multiforme (GBM) is the most common and lethal brain tumor. Its prognosis remains very poor, despite the use of combined treatments such as surgical resection, radiation and chemotherapy. The major limitations for the treatment of GBM are its high invasiveness, tumor recurrence and resistance to treatments. Therefore, gene therapy appears as a relevant strategy for its treatment. Thus, we have investigated the use of growth-arrest-specific 1 (Gas1) for the treatment of GBM. Gas1 is a tumor suppressor protein that inhibits glioma growth by inducing arrest and apoptosis of tumor cells. Moreover, we have shown that a soluble form of Gas1 acting in both autocrine and paracrine manners is also effective inhibiting tumor growth in animal models, indicating its potential as an adjuvant for the treatment of GBM.

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Activated Nrf2 impairs liver regeneration in mice by activation of genes involved in cell-cycle control and apoptosis

et al. 2014

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The nuclear factor erythroid-derived 2, like 2 (Nrf2) transcription factor is a key regulator of the antioxidant defense system, and pharmacological activation of Nrf2 is a promising strategy for prevention of toxin-induced liver damage. However, the consequences of Nrf2 activation on liver regeneration (LR) have not been determined. To address this question, we generated mice expressing a constitutively active Nrf2 (caNrf2) mutant in hepatocytes. Expression of the transgene did not affect liver homeostasis. Surprisingly, however, there was no beneficial effect of Nrf2 activation on CCl 4 -induced liver injury and fibrosis. Most important, LR after partial hepatectomy was impaired in caNrf2-transgenic mice as a result of delayed hepatocyte proliferation and enhanced apoptosis of these cells after liver injury. Mechanistically, this involved up-regulation of the cyclin-dependent kinase inhibitor p15 and the proapoptotic protein Bcl2l11 (Bim). Using chromatin immunoprecipitation, we show that the p15 and Bcl2l11 genes are direct targets of Nrf2, which are activated under hyperproliferative conditions in the liver. Conclusion: Activated Nrf2 delays proliferation and induces apoptosis of hepatocytes in the regenerating liver. These negative effects of Nrf2 activation on LR should be considered when Nrf2-activating compounds are used for prevention of liver damage. (HEPATOLOGY 2014;60:670-678) See Editorial on Page 461 T he use of oxygen as an electron acceptor confronts aerobic organisms with the danger of reactive oxygen species (ROS) being formed as by-products of the respiratory chain. ROS formation can be further enhanced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which are particularly abundant in inflammatory cells.1 Low levels of ROS are required for intracellular signaling, 2 but excessive levels damage all types of cellular macromolecules. To limit ROS-induced cell damage, aerobes developed strategies for efficient ROS detoxification. Of particular importance is the transcription factor nuclear factor erythroid-derived 2, like 2 (Nrf2), which controls expression of numerous genes encoding antioxidant proteins and ROS-detoxifying enzymes. 3Under homeostatic conditions, Nrf2 is retained in the cytoplasm by binding to Keap1, which also targets Nrf2 for proteasomal degradation. However, some Nrf2 molecules escape this inhibitory mechanism and translocate to the nucleus, where they bind to antioxidant response elements (AREs) in the promoter/ enhancer regions of their target genes. This leads to a basal expression of most Nrf2 target genes. In the

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GAS1 induces cell death through an intrinsic apoptotic pathway

Cited by 45 publications

References 36 publications

Growth Arrest Specific 1 (GAS1) Is Abundantly Expressed in the Adult Mouse Central Nervous System

Growth Arrest Specific 1 (GAS1) Is Abundantly Expressed in the Adult Mouse Central Nervous System

Effects of Gas1 on gliomas: a review on current preclinical studies

Activated Nrf2 impairs liver regeneration in mice by activation of genes involved in cell-cycle control and apoptosis

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