Hydrogen Peroxide Formation and Actin Filament Reorganization by Cdc42 Are Essential for Ethanol-induced in Vitro Angiogenesis

Qian, Yong; Luo, Jia; Leonard, Stephen S.; Harris, Gabriel K.; Millecchia, Lyndell; Flynn, Daniel C.; Shi, Xianglin

doi:10.1074/jbc.m207517200

Cited by 73 publications

(72 citation statements)

References 35 publications

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“…The wound healing assays were performed as described previously (Qian et al, 2003). Wounds were created in confluent LoVo cells in six-well plates by using a sterile pipette tips.…”

Section: Wound Healing Assaymentioning

confidence: 99%

PCAF Acetylates β-Catenin and Improves Its Stability

Jin

Zhang

et al. 2009

MBoC

104

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␤-Catenin plays an important role in development and tumorigenesis. However, the effect of a key acetyltransferase p300/CBP-associated factor (PCAF) on ␤-catenin signaling is largely unknown. In this study, we found PCAF could increase the ␤-catenin transcriptional activity, induce its nuclear translocation, and up-regulate its protein level by inhibiting its ubiquitination and improving its stability. Further studies showed that PCAF directly binds to and acetylates ␤-catenin. The key ubiquitination sites Lys-19 and Lys-49 of ␤-catenin were shown as the critical residues for PCAF-induced acetylation and stabilization. Knockdown of PCAF in colon cancer cells markedly reduced the protein level, transcriptional activity, and acetylation level of ␤-catenin; promoted cell differentiation; inhibited cell migration; and repressed xenografted tumorigenesis and tumor growth in nude mice. All these data demonstrate that PCAF acetylates ␤-catenin and regulates its stability, and they raise the prospect that therapies targeting PCAF may be of clinical use in ␤-catenin-driven diseases, such as colon cancer. INTRODUCTIONThe Wnt signaling pathway has important roles in a variety of developmental processes (Logan and Nusse, 2004;Clevers, 2006). The key output of this pathway is the stabilization and nuclear translocation of ␤-catenin, which determines the activation of ␤-catenin-responsive genes. Aberrant activation of Wnt signaling is often associated with carcinogenesis. Colorectal tumors are among most common human neoplasms, and Ͼ90% of colorectal cancers have a mutation that activates Wnt signaling (Giles et al., 2003;Doucas et al., 2005). Inactivating adenomatous polyposis coli (APC) mutations has been demonstrated in ϳ85% of sporadic colorectal tumors. Among the 15% colon carcinomas without APC mutations, ␤-catenin or the scaffolding protein Axin2 is mutant (Morin et al., 1997;Liu et al., 2000). Accumulating studies strongly suggest that disruption of Wnt signaling is a promising strategy for the prevention of colon cancers, and how to regulate the stability of ␤-catenin is the key point (Clapper et al., 2004;Dihlmann and von Knebel Doeber, 2005; DvorySobol et al., 2006).It is well known that Wnt signaling is regulated by phosphorylation. Besides phosphorylation, ubiquitination and acetylation have also been reported to be involved in Wnt signaling (Aberle et al., 1997;Sun et al., 2000;Takemaru and Moon, 2000;Winer et al., 2006). Lys-19 and Lys-49 of ␤-catenin were reported as important ubiquitination sites (Winer et al., 2006), and Lys-49 of ␤-catenin was also reported to be acetylated by CBP (Wolf et al., 2002). Whether there is some cross-talk between the ubiquitination and acetylation of ␤-catenin is yet to be elucidated. Some acetyltransferases such as CREB-binding protein (CBP)/p300 are related to colon cancer causation and progression (Muraoka et al., 1996;Ionov et al., 2004), and CBP/p300 can interact with ␤-catenin and synergistically activate ␤-catenin/T cell factor (TCF) transcription (Sun et al., 2000;Takema...

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“…The wound healing assays were performed as described previously (Qian et al, 2003). Wounds were created in confluent LoVo cells in six-well plates by using a sterile pipette tips.…”

Section: Wound Healing Assaymentioning

confidence: 99%

PCAF Acetylates β-Catenin and Improves Its Stability

Jin

Zhang

et al. 2009

MBoC

104

View full text Add to dashboard Cite

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“…10) Furthermore, there is increasing evidence of the involvement of H 2 O 2 in the regulation of angiogenesis. 9,[11][12][13] As well, a variety of cell lines derived from human tumors has been shown to produce large amounts of H 2 O 2 . 14) Constitutive surveillance for cellular protection against oxidative stress is conferred by intracellular antioxidative agents.…”

Section: )mentioning

confidence: 99%

Inhibitory Effect of Electrolyzed Reduced Water on Tumor Angiogenesis

Hamasaki

et al. 2008

Biological & Pharmaceutical Bulletin

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Tumor angiogenesis, the formation of new blood capillaries by vascular endothelial cells from existing vessels, is an important mechanism for supplying nutrients, oxygen, growth factors and others to tumor cells. Tumor cells trigger angiogenesis by secreting angiogenic factors, especially vascular endothelial growth factor (VEGF-A), 1) which plays an important role in the regulation of normal and abnormal angiogenesis.2) VEGF-A (commonly known as VEGF) was first reported as a vascular permeability-inducing factor secreted by tumor cells, and referred to as vascular permeability factor (VPF). Reactive oxygen species (ROS) are suggested to play an important role in angiogenesis. 10) Furthermore, there is increasing evidence of the involvement of H 2 O 2 in the regulation of angiogenesis.9,11-13) As well, a variety of cell lines derived from human tumors has been shown to produce large amounts of H 2 O 2 .14) Constitutive surveillance for cellular protection against oxidative stress is conferred by intracellular antioxidative agents.15) Excess amounts of ROS are toxic and cause a reduction of intracellular antioxidant levels.16) It has been reported that pretreatment of the heart with exogenous antioxidants improved its condition as a result of reducing ROS production.17) The VEGF-A gene is one that has its expression regulated by ROS, especially by H 2 O 2 . Additional data support that VEGF-A mRNA is up-regulated by H 2 O 2 in a dose-and time-dependent manner. 18,19) Taken together, these suggest that some endogenous as well as exogenous antioxidative agents can be used to regulate VEGF-A gene expression and/or H 2 O 2 production for therapeutic purposes.Electrolyzed reduced water (ERW) has attracted much attention because of its antioxidative potential. Water electrolysis typically produces two forms of water: reduced or alkaline (high pH) water near the cathode and an oxidized or acid (low pH) water near the anode. Applications of oxidized

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“…The wound healing assays were performed according to the methods described previously (Qian et al, 2003). Briefly, CEF cells were grown on coverslips to 100% confluent monolayers and then scratched to form a 100-mm 'wound' using sterile pipette tips.…”

Section: Wound Healing Assaymentioning

confidence: 99%

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

et al. 2005

Self Cite

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One of the hallmarks of integrin signaling is an increase in cell migration and invasion, both of which are associated with actin filament rearrangements. Integrin-linked kinase (ILK) is a cytoplasmic effector of integrin receptors. ILK is known to be involved in multiple cellular functions. However, the signaling pathways involved in ILKmediated cellular structure and motility remain to be elucidated. Here, we have demonstrated that overexpression of ILK was sufficient to induce actin filament rearrangements, to form cell motility structures, and to increase cell migration and invasion in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. This corresponds with the activation of both Akt and p70 ribosomal protein S6 kinase (p70S6K1). Overexpression of dominantnegative mutants of Akt inhibited ILK-dependent activation of p70S6K1, indicating that Akt is upstream of p70S6K1 in response to ILK signaling. Overexpression of ILK was sufficient to induce Rac1 activation, which was abolish by a PI3K inhibitor, indicating that Rac1 activity is involved in ILK signaling in a PI3K dependent manner. Inhibition of Akt, Rac1, or p70S6K1 inhibited the effects of ILK on actin filaments and cell migration, suggesting a regulatory role of the PI3K/Akt/p70S6K1/Rac1 signaling pathway in response to ILK signaling. We have shown that overexpression of a dominant-negative ILK was sufficient to abolish fibronectin peptide (PHSRN)-induced rearrangements of actin filaments and cell migration and invasion. Taken together, our results identify a mechanism through which ILK can regulate both integrin-associated rearrangements of actin filaments and cell migration and invasion at the integrin receptor-proximal region.

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Hydrogen Peroxide Formation and Actin Filament Reorganization by Cdc42 Are Essential for Ethanol-induced in Vitro Angiogenesis

Cited by 73 publications

References 35 publications

PCAF Acetylates β-Catenin and Improves Its Stability

PCAF Acetylates β-Catenin and Improves Its Stability

Inhibitory Effect of Electrolyzed Reduced Water on Tumor Angiogenesis

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

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