Evidence that the bifunctional redox factor / AP endonuclease Ref-1 is an anti-apoptotic protein associated with differentiation in the developing retina

Chiarini, Luciana B.; Freitas, Fabíola G. de; Petrs‐Silva, Hilda; Linden, Rafael

doi:10.1038/sj.cdd.4400639

Cited by 33 publications

(42 citation statements)

References 37 publications

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“…Moreover, overexpressing Ape1/Ref-1 in hippocampal and sensory cells results in a significant increase in cell viability after exposure to hydrogen peroxide (89). Preventing the loss of Ape1/Ref-1 by inhibiting protein synthesis rescued neurons from experimentally induced cell death (13). We have shown here that Ape1/Ref-1 expression led to enhancement of neuronal differentiation and survival (Fig.…”

Section: Discussionmentioning

confidence: 59%

Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor α1 Expression

Kim

Acharya

et al. 2009

Molecular and Cellular Biology

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The major human apurinic and apyrimidinic (AP) endonuclease 1 Ape1 (also known as Redox factor 1 [Ref-1]), which is homologous to Escherichia coli exonuclease III, plays a key role in both short-patch and long-patch base excision repair (20,40). It cleaves the AP sites in DNA and allows them to be repaired by other enzymes involved in base excision repair (16,23,24). The AP sites can be formed by chemical hydrolysis, the oxygen metabolism, ionizing radiation, UV irradiation, alkylating agents, or oxidizing agents (16,53). In addition, AP sites can also arise spontaneously, where it has been estimated that 20,000 purine samples and 500 pyrimidines are lost in each 24-h cell cycle in human cells (52). The presence of AP sites blocks DNA replication, leading to DNA breakage, mutagenicity, and cytotoxicity. Ape1/Ref-1 contributes to more than 95% of the total cellular AP site-specific activity (12), which is consistent with Ape1/Ref-1 being essential for maintaining the genomic stability. (32,35,73). Studies have reported elevated Ape1/Ref-1 levels or altered subcellular localization in various types of cancers, such as epithelial ovarian cancers, cervical cancers, prostate cell tumors, melanoma, gliomas, rhabdomyosarcoma, and germ cell tumors, which are associated with tumor resistance and progression (7,21,22,43,74,99,100). Ape1/Ref-1 is highly expressed in selected regions of the central nervous system (68,95). A reduction in Ape1/ Ref-1 expression occurs in the hippocampus after hypoxicischemic injury (93), in the cortex after compression injury (49), and in the spinal cord after ischemia (76). In addition,

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Section: Discussionmentioning

confidence: 59%

Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor α1 Expression

Kim

Acharya

et al. 2009

Molecular and Cellular Biology

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“…Previous work from our laboratory showed that thapsigargin selectively kills photoreceptors in the outer nuclear layer of retinal explants from 1-week-old rats (33). The degeneration of rhodopsin-containing photoreceptors was also prevented by PACAP38 (Fig.…”

Section: Pacap38 Is a Potent Neuroprotective Agent In The Newbornmentioning

confidence: 59%

“…Counts of pyknotic profiles were made at ϫ1000 magnification under oil immersion in three random fields of 0.0148 mm 2 within the neuroblastic layer, and at least three randomly selected explants were analyzed for each group in each experiment. Photoreceptor cell death was identified by the round and condensed morphology of rhodopsin-positive profiles within the outer nuclear layer, wherein normal photoreceptors present an elongated shape at that age (33). Counts were made at ϫ1000 magnification under oil immersion in three random fields of 0.0074 mm 2 within the outer nuclear layer.…”

Section: Methodsmentioning

confidence: 99%

Pituitary Adenylyl Cyclase-activating Polypeptide Prevents Induced Cell Death in Retinal Tissue through Activation of Cyclic AMP-dependent Protein Kinase

Silveira

Costa

Bozza

et al. 2002

Journal of Biological Chemistry

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Multiple neuroactive substances are secreted by neurons and/or glial cells and modulate the sensitivity to cell death. In the developing retina, it has been shown that increased intracellular levels of cAMP protect cells from degeneration. We tested the hypothesis that the neuroactive peptide pituitary adenylyl cyclase-activating polypeptide (PACAP) has neuroprotective effects upon the developing rat retina. PACAP38 prevented anisomycin-induced cell death in the neuroblastic layer (NBL) of retinal explants, and complete inhibition of induced cell death was obtained with 1 nM. A similar protective effect was observed with PACAP27 and with the specific PAC1 receptor agonist maxadilan but not with glucagon. Photoreceptor cell death induced by thapsigargin was also prevented by PACAP38. The neuroprotective effect of PACAP38 upon the NBL could be reverted by the competitive PACAP receptor antagonist PACAP6 -38 and by the specific PAC1 receptor antagonist Maxd.4. Molecular and immunohistochemical analysis demonstrated PAC1 receptors, and treatment with PACAP38 induced phospho-cAMP-response elementbinding protein immunoreactivity in the anisomycinsensitive undifferentiated postmitotic cells within the NBL. PACAP38 produced an increase in cAMP but not inositol triphosphate, and treatment with the cAMP-dependent protein kinase inhibitor R p -cAMPS blocked the protective effect of PACAP38. The results indicate that activation of PAC1 receptors by PACAP38 modulates cell death in the developing retina through the intracellular cAMP/cAMP-dependent protein kinase pathway.Developmental cell death is a major event in neurogenesis, controlled by various secreted molecules, many of which play distinct roles in the mature nervous system. Identification of neuroprotective molecules is relevant both for embryogenesis as well as for studies of neurodegenerative diseases because the modes of cell death and many upstream control pathways appear to be conserved among both normal and pathological conditions (1). Classically, neuroprotection is attributed to neurotrophic proteins such as the neurotrophin family of growth factors (for a review, see Refs. 2 and 3), but many lines of evidence support the involvement of both classical neurotransmitters and neuropeptides in the control of cell death (4,5).The retina of newborn rats is composed of two cellular strata separated by the inner plexiform layer. The innermost cellular stratum is the ganglion cell layer, the long axons of which form the optic nerve. On the opposite side of the inner plexiform layer, the outer cellular stratum contains a few rows of early developing amacrine cells in the inner nuclear layer. The remainder of the outer stratum constitutes the neuroblastic layer (NBL), 1 which corresponds to the ventricular zone, in which high proliferative activity persists postnatally (6). In addition to the proliferating neuroblasts, the NBL in newborn rats contains undifferentiated postmitotic cells that are migrating toward their final destinations across the depth of the retinal ti...

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“…Both of these two activities seem to be fundamental in the works (14,96,126). APEl/Ref-1 expression is always inversely correlated with the onset of apoptosis, suggesting a role as an antiapoptotic molecule.…”

Section: General Considerations Onapel/ref-1 Biological and Molecularmentioning

confidence: 99%

The Intracellular Localization of APE1/Ref-1: More than a Passive Phenomenon?

Tell

Damante

Caldwell

et al. 2005

Antioxidants & Redox Signaling

355

397

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Human apul'inic/apyrimidinic endonuclease l/redox effector factor-1 (APEl/Ref·l) is a perfect paradigm of the functional complexity of a biological macromolecule. First, it plays a crucial role, by both redox-dependent and -independent mechanisms, as a transcriptional coactivator for different trnnscription factors, either ubiquitous (i.e., AP-1, Egr-1, NF-KB, p53, HIF) or tissue-specific (i.e., PEBP-2, Pax-Sand -8, TTF-1), in controlling different cellular processes such as apoptosis, proliferation, and differentiation. Second, it acts, as an apurinidapyrimidinic endonuclease, during the second step of the DNA base excision repair pathway, which is responsible for the repair of cellular alkylation and oxidative DNA damages. Thil'd, it controls the intracellular reactive oxygen species production by negatively regulating the activity of the Ras-related GTPase Rael. Despite these known functions of APEl/Ref-1, information is still scanty about the molecular mechanisms responsible for the coordinated control of its several activities. Some evidence suggests that the expression and subcellular localization of APEl/Ref-1 are finely tuned. APEl/Ref-1 is a ubiquitous protein, but its expression pattern differs according to the different cell types. APEl/Ref-1 subcellular localization is mainly nuclear, but cytop1asmic staining has also been reported, the latter being associated with mitochondria and/or presence within the endoplasmic reticulum. It is not by chance that both expression and sub cellular localization a1·e altered in several metabolic and proliferative disorde1·s, such as in tumors and aging. Moreover, a fundamental role played by different posttranslational modifications in modulating APEl/Ref·l functional activity is becoming eYident. In the present review, we tded to put togethe1· a growing body of information concerning APEl/Ref-l's different functions, shedding new light on present and future directions to understand fully this unique molecule. Antioxid. Redox Signal. 7,[367][368][369][370][371][372][373][374][375][376][377][378][379][380][381][382][383][384]

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Evidence that the bifunctional redox factor / AP endonuclease Ref-1 is an anti-apoptotic protein associated with differentiation in the developing retina

Cited by 33 publications

References 37 publications

Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor α1 Expression

Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor α1 Expression

Pituitary Adenylyl Cyclase-activating Polypeptide Prevents Induced Cell Death in Retinal Tissue through Activation of Cyclic AMP-dependent Protein Kinase

The Intracellular Localization of APE1/Ref-1: More than a Passive Phenomenon?

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