A Mechanism of Cell Survival

Wang, Xue; DeFrances, Marie C.; Dai, Yu; Pediaditakis, Peter; Johnson, Carla J.; Bell, Aaron; Michalopoulos, George K.; Zarnegar, Reza

doi:10.1016/s1097-2765(02)00439-2

Cited by 201 publications

(55 citation statements)

References 26 publications

(3 reference statements)

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“…9A). Previous work suggested that Met-mediated prevention of apoptosis could be independent from its catalytic activity (15). Our data clearly indicate that the mechanisms by which Met triggers the antiapoptotic response are also strictly reliant on its kinase activity.…”

Section: Resultssupporting

confidence: 74%

Genetic targeting of the kinase activity of the Met receptor in cancer cells

Arena

Pisacane²,

Mazzone

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The development of kinase inhibitors is revolutionizing cancer treatment. Assessing the oncogenic potential of individual kinase activities and ensuring that a drug of interest acts by direct inhibition of its putative target kinase are clear priorities. We developed a genetic strategy to selectively inactivate the catalytic activity of kinases. This approach generates isogenic cells in which a given kinase gene is expressed but is devoid of enzymatic activity. As a model to test this approach, we chose the MET receptor, which is involved in multiple cancers and is the focus of several therapeutic efforts. The exon encoding the ATP-binding site of MET was deleted from the genome of colorectal, bladder, and endometrial cancer cells. The derivative isogenic cells expressed a kinase-inactive Met (MET-KD) and were completely unresponsive to its ligand hepatocyte growth factor (HGF), indicating the exclusivity of this ligand-receptor axis. The in vivo tumorigenic potential of MET-KD cells was reduced but could be partially restored by HGF, suggesting that concomitant targeting of the receptor and its ligand should be therapeutically exploited. A reportedly selective Met-kinase inhibitor (SU-11274) markedly affected the growth of MET-KD cancer cells, indicating this compound exerts its effects not only through the intended target. The genetic strategy presented here is not limited to kinase genes but could be broadly applicable to any drug/protein combination in which the target enzymatic domain is known.knockout ͉ somatic knockout ͉ targeted therapy ͉ kinase inhibitor ͉ invasive growth

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Section: Resultssupporting

confidence: 74%

Genetic targeting of the kinase activity of the Met receptor in cancer cells

Arena

Pisacane²,

Mazzone

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…To test vulnerability to injury, we first evaluated the response of MetLivKO mice to apoptotic stimuli induced by Fas antibody. This was of considerable interest because not only does pretreatment with rhHGF before anti-Fas antibody injection demonstrate a potent dose-dependent inhibition of liver apoptosis and lethal hepatic failure (19), but it was recently shown that direct binding between c-Met and Fas receptor inhibited Fas activation and thus prevented apoptosis (28). Massive hepatocyte death and hemorrhagic liver destruction in MetLivKO mice began within the first 2-4 h after injection of the Jo-2 antibody; and by 8 h, 80% of the animals died of acute liver failure.…”

Section: Resultsmentioning

confidence: 99%

“…2 D-F ), implying that Fas expression is not affected by the lack of c-Met under physiological conditions. However, the observed sensitivity of the MetLivKO mice to Fas-mediated apoptosis may be due to the reduced amount of c-Met protein and thus attenuated Met-Fas sequestration (28). Alternatively, the loss of antiapoptotic signaling by HGF͞c-met in MetLivKO mice may potentiate the death-inducing function of the Fas ligand (29).…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte growth factor/c-metsignaling pathway is required for efficient liver regeneration and repair

Huh

Factor

Sánchez

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

681

563

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Hepatocyte growth factor͞scatter factor c-met signaling pathway is of central importance during development as well as in tumorigenesis. Because homozygous null mice for either hgf͞sf or c-met die in utero, we used Cre͞loxP-mediated gene targeting to investigate the function of c-met specifically in the adult liver. Loss of c-met appeared not to be detrimental to hepatocyte function under physiological conditions. Nonetheless, the adaptive responses of the liver to injury were dramatically affected. Mice lacking c-met gene in hepatocytes were hypersensitive to Fas-induced apoptosis. When injected with a low dose of antiFas antibody, the majority of these mice died from massive apoptosis and hemorrhagic necrosis, whereas all wild-type mice survived with signs of minor injury. After a challenge with a single necrogenic dose of CCl 4 , c-met conditional knockout mice exhibited impaired recovery from centrolobular lesions rather than a deficit in hepatocyte proliferation. The delayed healing was associated with a persistent inflammatory reaction, overproduction of osteopontin, early and prominent dystrophic calcification, and impaired hepatocyte scattering͞migration into diseased areas. These studies provide direct genetic evidence in support of the critical role of c-met in efficient liver regeneration and suggest that disruption of c-met affects primarily hepatocyte survival and tissue remodeling.

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“…Two decades ago, profound studies were published about the physiological aspects of HGF in health and development [29,30]. In recent years, however, several groups have focused on assessing HGF during inflammation and cancer [10].…”

Section: Discussionmentioning

confidence: 99%

Differences in the expression of hepatocyte growth factor in acute and chronic bowel inflammation—Implications for diagnosis?

Lönn¹,

Nakka²,

Olsson³

et al. 2013

ABB

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Background: Hepatocyte growth factor (HGF) acts as an acute phase protein with regenerative properties. HGF is produced systemically and locally during inflammation but exhibits decreased binding affinity to heparan sulphate proteoglycan (HSPG)/glycosaminoglycan during chronic inflammation. We previously observed a high faecal concentration and binding affinity of HGF to HSPG during acute gastroenteritis. High faecal concentrations of calprotectin and HGF have been reported in chronic inflammatory bowel disease (IBD). Methods: Stool samples from patients with ulcerative colitis in remission (n = 11) or exacerbation (n = 5), microscopic colitis (n = 11), colon cancer (n = 6), or acute gastroenteritis caused by Clostridium difficile (n = 20), as well as healthy controls (n = 7), were analysed for the presence of HGF by ELISA, surface plasmon resonance, SDS-PAGE, and Western blot. Then in two patients with ulcerative colitis exacerbation and C. difficile infection, the expression of HGF and calprotectin was studied in colonic biopsies. Results: The faecal concentration of HGF was significantly higher in patients with ulcerative colitis compared to the other groups. The binding affinity to dextran was lower in all groups compared to acute inflammation. HGF receptor binding was similar across groups. In a patient with concomitant C. difficile infection and distal ulcerative colitis, HGF was highly expressed in the part of the bowel unaffected by ulcerative colitis, but no expression was found at the site of chronic inflammation. In the patient with total colitis the biopsies showed low expression of HGF. The areas with chronic inflammation exhibited infiltrating calprotectin-stained neutrophils. Conclusion: HGF is produced locally during inflammation of the bowel. The HGF produced during acute inflammation or exacerbations of chronic inflammation by the unaffected area shows binding affinity to glucosaminoglycans. Measuring HGF binding in faeces and biopsies may be a tool for differentiating between acute and chronic bowel inflammation, which should be assessed thoroughly in future studies.

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A Mechanism of Cell Survival

Cited by 201 publications

References 26 publications

Genetic targeting of the kinase activity of the Met receptor in cancer cells

Genetic targeting of the kinase activity of the Met receptor in cancer cells

Hepatocyte growth factor/c-metsignaling pathway is required for efficient liver regeneration and repair

Differences in the expression of hepatocyte growth factor in acute and chronic bowel inflammation—Implications for diagnosis?

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