GADD45 Proteins: Central Players in Tumorigenesis

Tamura, Rodrigo Esaki; Vasconcellos, Jaira F. de; Sarkar, Devanand; Libermann, Towia A.; Fisher, Paul B.; Zerbini, Luiz Fernando

doi:10.2174/156652412800619978

Cited by 273 publications

(228 citation statements)

References 171 publications

(203 reference statements)

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“…26,27 The increased expression of these two antiproliferation FoxO targets could also contribute to antineoplastic and antigenotoxic effects of cGMP signaling, which have been reported previously. 21,53,54 FoxO3a could therefore serve many functions in the differentiated colon epithelium, but we demonstrated herein that it can protect these cells from oxidative stress, as has been described recently for quiescent cells. 33 FoxO expression at the luminal border would therefore augment epithelial barrier resiliance to the destructive effects of ROS that are known to be generated by commensal bacteria.…”

Section: Pkg2 Activates Foxo3a In the Colonsupporting

confidence: 75%

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Wang

Islam

Bridges

et al. 2017

The American Journal of Pathology

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Signaling through cGMP has therapeutic potential in the colon, where it has been implicated in the suppression of colitis and colon cancer. In this study, we tested the ability of cGMP and type 2 cGMPdependent protein kinase (PKG2) to activate forkhead box O (FoxO) in colon cancer cells and in the colon epithelium of mice. We show that activation of PKG2 in colon cancer cells inhibited cell proliferation, inhibited AKT, and activated FoxO. Treatment of colon explants with 8Br-cGMP also activated FoxO target gene expression at both RNA and protein levels, and reduced epithelial reduction-oxidation (redox) stress. FoxO3a was the most prominent isoform in the distal colon epithelium, with prominent luminal staining. FoxO3a levels were reduced in Prkg2 À/À animals, and FoxO target genes were unaffected by 8Br-cGMP challenge in vitro. Treatment of mice with the phosphodiesterase-5 inhibitor vardenafil (Levitra) mobilized FoxO3a to the nucleus of luminal epithelial cells, which corresponded to increased FoxO target gene expression, reduced redox stress, and increased epithelial barrier integrity. Treatment of human colonic biopsy specimens with 8Br-cGMP also activated catalase and manganese superoxide dismutase expression, indicating that this pathway is conserved in humans. Taken together, these results identify a novel signaling pathway in the colon epithelium, where FoxO tumor suppressors could provide protection from redox stress. Moreover, this pathway is regulated by endogenous cGMP/PKG2 signaling, and can be targeted using phosphodiesterase-5 inhibitors. (Am J Pathol 2017, 187: 377e389; http://dx

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Section: Pkg2 Activates Foxo3a In the Colonsupporting

confidence: 75%

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Wang

Islam

Bridges

et al. 2017

The American Journal of Pathology

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“…Functions of GADD45 family proteins are similar, but not identical, and their induction differs under diverse physiological conditions or in different cell types. 43 GADD45A, one of the most critical downstream targets of tumor suppressor TP53 and BRCA1, 44 45,46 Hence, these findings prompted us to study whether GADD45A can induce an autophagy response and what is the underlying mechanism. In this study, through western blot and immunofluorescence assays for specific markers of the autophagic system, we found that the number of autophagosomes in GADD45A knockout mice and MEF cells significantly increased as a result of GADD45A deletion.…”

Section: Gadd45gmentioning

confidence: 99%

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

Zhang

et al. 2015

Autophagy

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Abbreviations: ACTB/b-actin, actin, beta; ATG, autophagy-related, Baf, bafilomycin A 1 ; BECN1, Beclin 1, autophagy related; DAPI, 4 0 ,6-diamidino-2-phenylindol dihydrochloride; DNA, deoxyribose nucleic acid; GADD45A, growth arrest and DNA-damage-inducible, alpha; GFP, green fluorescent protein; GST, glutathione s-transferase; LC3/MAP1LC3, microtubule-associated protein 1 light chain 3; MEFs, mouse embryonic fibroblasts; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PIK3C3, phosphatidylinositol 3-kinase, catalytic subunit type 3; RFP, red fluorescent protein; SDS, sodium dodecyl sulfate; SQSTM1, sequestosome 1; UVR, ultraviolet radiation GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A 1 treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation.

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“…GADD45 is one of the growth arrest and DNA-damage-inducible genes (GADD) that plays a pivotal role in cellular genotoxic and nongenotoxic stress responses, acting as stress sensor and tumor suppressors. 41 Studies have shown that cells exhibit uncontrolled proliferation when GADD45 is repressed. 42 Altogether, the results presented here show that TiO 2 nanofibrous surface structures could account for their morphogenic effect in triggering cell proliferation and regulating normal cell cycle progression.…”

mentioning

confidence: 99%

Proliferation and stemness preservation of human adipose-derived stem cells by surface-modified in situ TiO2 nanofibrous surfaces

Tan¹,

Tay²,

Chua³

et al. 2014

IJN

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Two important criteria of an ideal biomaterial in the field of stem cells research are to regulate the cell proliferation without the loss of its pluripotency and to direct the differentiation into a specific cell lineage when desired. The present study describes the influence of TiO 2 nanofibrous surface structures on the regulation of proliferation and stemness preservation of adipose-derived stem cells (ADSCs). TiO 2 nanofiber arrays were produced in situ onto Ti-6Al-4V substrate via a thermal oxidation process and the successful fabrication of these nanostructures was confirmed by field emission scanning electron microscopy (FESEM), energy dispersive spectrometer (EDS), X-ray diffractometer (XRD), and contact angle measurement. ADSCs were seeded on two types of Ti-6Al-4V surfaces (TiO 2 nanofibers and flat control), and their morphology, proliferation, and stemness expression were analyzed using FESEM, AlamarBlue assay, flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR) after 2 weeks of incubation, respectively. The results show that ADSCs exhibit better adhesion and significantly enhanced proliferation on the TiO 2 nanofibrous surfaces compared to the flat control surfaces. The greater proliferation ability of TiO 2 nanofibrous surfaces was further confirmed by the results of cell cycle assay. More importantly, TiO 2 nanofibrous surfaces significantly upregulate the expressions of stemness markers Sox-2, Nanog3, Rex-1, and Nestin. These results demonstrate that TiO 2 nanofibrous surfaces can be used to enhance cell adhesion and proliferation while simultaneously maintaining the stemness of ADSCs, thereby representing a promising approach for their potential application in the field of bone tissue engineering as well as regenerative therapies.

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GADD45 Proteins: Central Players in Tumorigenesis

Cited by 273 publications

References 171 publications

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

Proliferation and stemness preservation of human adipose-derived stem cells by surface-modified in situ TiO2 nanofibrous surfaces

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GADD45 Proteins: Central Players in Tumorigenesis

Cited by 273 publications

References 171 publications

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

Proliferation and stemness preservation of human adipose-derived stem cells by surface-modified in&nbsp;situ TiO2 nanofibrous surfaces

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Proliferation and stemness preservation of human adipose-derived stem cells by surface-modified in situ TiO2 nanofibrous surfaces