The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase

Fan, Saijun; Xian, Yong; Wang, Ji An; Ren, Yuan; Meng, Qinghui; Cao, Yijan; Laterra, John; Goldberg, Itzhak D.; Rosen, Eliot M.

doi:10.1038/sj.onc.1203566

Cited by 150 publications

(135 citation statements)

References 46 publications

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…This finding is consistent with our previous studies indicating a role for PI3K/c-Akt signaling in SF-mediated cell protection (Bowers et al, 2000;Fan et al, 2000Fan et al, , 2001Fan et al, , 2005, and it suggests that Ras acts, in part, upstream of PI3K in the cell protection pathway. The increased activity of V12C40Ras relative to V12Ras is consistent with an inhibitory component of Ras signaling owing to another pathway downstream of Ras (e.g., RalA) that is active in V12Ras but not in V12C40Ras.…”

Section: Discussionsupporting

confidence: 93%

“…Our previous studies indicate that c-Akt signaling is required for SF-mediated NF-kB activation and cell protection (Bowers et al, 2000;Fan et al, 2000Fan et al, , 2001Fan et al, , 2005. The present study revealed that DN-Akt also blocks the ability of RasV12 to enhance the SFstimulated NF-kB activity, suggesting that both Raf1 and c-Akt act downstream of Ras in the SF survival pathway.…”

Section: Discussionsupporting

confidence: 59%

“…This pathway involves signaling through phosphatidylinositol-3-kinase (PI3K) and activation of c-Akt, a serine/threonine protein kinase (Bowers et al, 2000;Fan et al, 2000Fan et al, , 2001. The p21-associated kinase-1 (Pak1) acts downstream of c-Akt to promote cell survival; and nuclear factor-kappa B (NF-kB) and several of its target genes are downstream of these kinases in the SF-protection pathway (Fan et al, 2001(Fan et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage

et al. 2007

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage

et al. 2007

View full text Add to dashboard Cite

“…HGFR activation protects from apoptosis in several tumor in vitro models (Bowers et al, 2000;Fan et al, 2000Fan et al, , 2005Gao et al, 2001;Zeng et al, 2002;Derksen et al, 2003;Lal et al, 2005), and activation of b-catenin promotes the transcription of antiapoptotic genes (Dihlmann et al, 2005;Kim et al, 2005;Ma et al, 2005) and was associated with increased tumor cell survival in CRC (Ireland et al, 2004;Ougolkov et al, 2004). However, a proapoptotic role of HGF (Arakaki et al, 1998;Matteucci et al, 2003;Rasola et al, 2004) and b-catenin (Kim et al, 2000;van Gijn et al, 2001;Edlund et al, 2005) was also reported in several models.…”

Section: Discussionmentioning

confidence: 99%

A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

et al. 2006

View full text Add to dashboard Cite

Overexpressed or activated hepatocyte growth factor receptor, encoded by the MET proto-oncogene, was found in the majority of colorectal carcinomas (CRCs), whose stepwise progression to malignancy requires transcriptional activation of b-catenin. We here demonstrate that a functional crosstalk between Met and b-catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts b-catenin tyrosine phosphorylation and dissociation from Met, and upregulates b-catenin expression via the phosphatidylinositol 3-kinase pathway in conditions that mimic those found by the invading and metastasizing cells. Additionally, a transcriptionally active form of b-catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the b-catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic b-catenin. In the mirror experiments, either Met or b-catenin knocking down also reduces their protein level. In biological assays, b-catenin knocking down abrogates the HGF-induced motile phenotype, whereas active b-catenin fosters ligand-independent cell scattering. Met and b-catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and b-catenin pathways are mutually activated in CRC cells. This might generate a selfamplifying positive feedback loop resulting in the upregulation of the invasive growth properties of CRC cells.

show abstract

“…We found that SF stimulates antiapoptotic signaling from the c-Met receptor to phosphatidylinositol-3 0 -kinase (PI3K) and the cell survival-promoting serine/threonine kinase c-Akt (Bowers et al, 2000;Fan et al, 2000Fan et al, , 2001. The multisubstrate adapter Gab1 (Grb2-associated binder-1) and the tumor suppressor PTEN (phosphatase and tensin homolog) act as upstream inhibitors of c-Akt to block SF-mediated cell protection, whereas Pak1 (p21-associated kinase-1) acts downstream of c-Akt to mediate cell protection .…”

Section: Introductionmentioning

confidence: 99%

Effect of Akt inhibition on scatter factor-regulated gene expression in DU-145 human prostate cancer cells

Gao

Fan

et al. 2006

Oncogene

View full text Add to dashboard Cite

The cytokine scatter factor (SF) (hepatocyte growth factor) transduces various biologic actions, including cell motility, invasion, angiogenesis and apoptosis inhibition. The latter is relevant to understanding the role of SF in promoting tumor cell survival in different contexts, for example, detachment from basement membrane, growth in metastatic sites and responses to chemo-and radiotherapy. Previously, we showed that SF protects cells against apoptosis owing to DNA damage, by a mechanism involving phosphoinositol-3-kinase/c-Akt signaling. Here, we used DNA microarray assays to identify c-Aktregulated genes that might contribute to cell protection. DU-145 human prostate cancer cells were transfected7a dominant-negative mutant Akt, treated7SF and analysed for gene expression using Affymetrix arrays. These studies identified SF-regulated genes for which induction was c-Akt-dependent vs -independent. Selected microarray findings were confirmed by semiquantitative and quantitative reverse transcription-polymerase chain reaction. We tested the contribution of four SF-inducible/ c-Akt-dependent genes (AMPD3, EPHB2, MX1 and WNT4) to protection against adriamycin (a DNA topoisomerase IIa inhibitor) using RNA interference. Knockdown of each gene except EPHB2 caused a small but significant reduction in the SF cell protection. The lack of effect of EPHB2 knockdown may be due to the fact that DU-145 cells contain a single-mutant EPHB2 allele. A combination of three small interfering RNAs blocked most of the protection by SF in both DU-145 and T47D cells. These findings identify novel c-Akt-regulated genes, some of which contribute to SF-mediated cytoprotection.

show abstract

The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase

Cited by 150 publications

References 46 publications

Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage

Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage

A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

Effect of Akt inhibition on scatter factor-regulated gene expression in DU-145 human prostate cancer cells

Contact Info

Product

Resources

About