Heterogeneity in c-jun Gene Expression in Normal and Malignant Cells Exposed to Either Ionizing Radiation or Hydrogen Peroxide

Seo

Journal of Biological Chemistry

et al. 2008

Heterotrimeric stimulatory GTP-binding protein (G s ) stimulates adenylate cyclases to activate the cAMP signaling pathway. Although the cAMP pathway has been reported to be involved in apoptosis, the role of the G s -cAMP signaling pathway during reactive oxygen species (ROS)-mediated apoptosis, which is involved in the resistance of cancer cells to chemotherapy and radiation, is not clearly understood. Thus, in this study we aimed to investigate the role of the ␣ subunit of G s (G␣ s The heterotrimeric GTP-binding proteins (G proteins) 2 are composed of ␣, ␤, and ␥ subunits, and the ␣ subunits of G protein (G␣) are classified into four main families: G␣ s , G␣ i , G␣ q , and G␣ 12 . When a signaling molecule, such as a hormone or a neurotransmitter binds to a G protein-coupled receptor (GPCR), the receptor stimulates the replacement of GDP with GTP on the G␣. GTP-bound activated heterotrimer dissociates into an ␣ subunit (G␣-GTP) and a ␤␥ dimer (G␤␥), which can independently regulate effectors including adenylate cyclases, phospholipases, phosphodiesterases, and ion channels. The hydrolysis of GTP to GDP by intrinsic GTPase, a process that is regulated by RGS (regulator of G-protein signaling) proteins, leads to the reassociation of the heterotrimer and the termination of the activation cycle (1-3). G protein signaling systems are involved in regulation of a variety of cellular responses, which include metabolism, neurotransmission, proliferation, differentiation, and apoptosis. Although signaling for cellular proliferation and apoptosis has generally been attributed to growth factor receptors that possess ligand-regulated protein-tyrosine kinase activity, growing evidence now indicates that GPCRs also regulate cellular growth and apoptosis (4 -6).Reactive oxygen species (ROS) are constantly generated under normal conditions as a consequence of aerobic metabolism, and the most common ROS types are superoxide anions (O .2 ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (HO Ϫ ) (7). ROS can react with DNA, proteins, carbohydrates, and lipids in a destructive manner due to their high levels of chemical reactivity. Thus, ROS are considered DNA-damaging agents that increase mutation rates and promote oncogenic transformation, and are implicated in the development of cancer and metastases (8, 9). Moreover, ROS participate in the modulation of apoptosis following treatment with various agents including Fas, ultraviolet, and chemotherapeutic drugs (10 -12). Therefore, the ability of a cancer cell to defend itself against ROS is associated with resistance to chemo-and radiotherapy. Consequently, a more detailed understanding of the mechanisms that regulate ROS-induced apoptosis would contribute to our abilities to develop novel therapeutic strategies directed toward killing resistant cancer cells (13).

Section: Discussionmentioning

confidence: 72%

Stimulatory Heterotrimeric GTP-binding Protein Inhibits Hydrogen Peroxide-induced Apoptosis by Repressing BAK Induction in SH-SY5Y Human Neuroblastoma Cells

Seo

Journal of Biological Chemistry

et al. 2008

“…In addition, AP-1 behaves as a redoxsensitive transcription factor in several cell types and is activated, to different extents, under prooxidant conditions generated by treatment with agents such as superoxide, H 2 O 2 , UV light, ␥-irradiation, and cytokines. [117][118][119][120][121] In cell types of the vasculature, AP-1 is similarly activated by prooxidant stimulus. In ECs, agents such as H 2 O 2 , 122 LDL, 123 and oxLDL 124 activate AP-1 DNA binding activity.…”

Section: Redox Regulation Of Ap-1mentioning

confidence: 99%

Oxidative Stress as a Regulator of Gene Expression in the Vasculature

Kunsch

Medford

1999

Circulation Research

732

517

Abstract-Oxidative stress and the production of intracellular reactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of diseases. In excess, ROS and their byproducts that are capable of causing oxidative damage may be cytotoxic to cells. However, it is now well established that moderate amounts of ROS play a role in signal transduction processes such as cell growth and posttranslational modification of proteins. Oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state play an important role in the regulation of gene expression. Recent insights into the etiology and pathogenesis of atherosclerosis suggest that this disease may be viewed as an inflammatory disease linked to an abnormality in oxidation-mediated signals in the vasculature. In this review, we summarize the evidence supporting the notion that oxidative stress and the production of ROS function as physiological regulators of vascular gene expression mediated via specific redox-sensitive signal transduction pathways and transcriptional regulatory networks. Elucidating, at the molecular level, the regulatory processes involved in redox-sensitive vascular gene expression represents a foundation not only for understanding the pathogenesis of atherosclerosis and other inflammatory diseases but also for the development of novel therapeutic treatment strategies.(Circ Res. 1999;85:753-766.)

“…AP-1 involvement in death of irradiated cells is probably an important protection against carcinogenesis, as it was found that stress-inducible fos and jun activation is lacking in many radioresistant tumour cell lines. This was demonstrated at the RNA level and DNA binding level for melanoma cells (Sahijdak et al, 1994;Collart et al, 1995), and at the RNA level for astrocytoma cell lines (Gubitz et al, 1993).…”

Section: Ap-1 and Tgf-b1 Coactivation In Irradiated Skin M Martin Et Almentioning

confidence: 99%

Coactivation of AP-1 activity and TGF-β1 gene expression in the stress response of normal skin cells to ionizing radiation

et al. 1997

Activation of the AP-1 transcription factor and TGF-b1 growth factor by ionizing radiation was studied both in vivo in pig skin, and in vitro in human ®broblasts and keratinocytes. Three and 6 h after irradiation, the Fos and Jun proteins and their binding activity to an AP-1 consensus sequence were strongly induced by high doses of g-rays. c-Fos, c-Jun and JunB proteins were found to be present in gel-shift complexes by probing with speci®c antibodies. Both keratinocytes and ®broblasts exhibited heightened AP-1 activity following irradiation. As we previously found that TGF-b1 is involved in the development of skin lesions induced by radiation, TGFb1 gene expression was also examined. Two and 6 h after irradiation, the levels of TGF-b1 transcripts were increased in skin. By immunostaining, TGF-b1 protein levels were found to be increased in ®broblasts, keratinocytes and endothelial cells. As the TGF-b1 promoter contains AP-1 binding sites, the relation between AP-1 activity and TGF-b1 induction was addressed. The 7365 TGF-b1 promoter fragment, which contains a high anity AP-1 site, exhibited increased binding to Jun and Fos proteins following irradiation. These results suggest that stress-inducible TGF-b1 expression is mediated by the activation of AP-1 transcription factor.