Inhibition of radiation-induced transformation of C3H/10T½ cells by chymotrypsin inhibitor 1 from potatoes

Billings, Paul C.; Clair, William St; Ryan, Austin T.; Kennedy, Ann R.

doi:10.1093/carcin/8.6.809

Cited by 31 publications

(5 citation statements)

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“…Proteinase inhibitors from plants have been known for some time to have anticarcinogenic properties (29) and potato Inh I had been shown to inhibit carcinogen-induced transformation of C3H͞10T 1 ⁄2 cells by x-irradiation (30). Inh I and Inh II were also found to be the most potent among several inhibitors of the formation of H 2 O 2 in polymorphonuclear leukocytes, activated by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (31).…”

Section: Resultsmentioning

confidence: 99%

Proteinase inhibitors I and II from potatoes specifically block UV-induced activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase

Huang

Ryan

et al. 1997

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

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Solar UV irradiation is the causal factor for the increasing incidence of human skin carcinomas. The activation of the transcription factor activator protein-1 (AP-1) has been shown to be responsible for the tumor promoter action of UV light in mammalian cells. We demonstrate that proteinase inhibitor I (Inh I) and II (Inh II) from potato tubers, when applied to mouse epidermal JB6 cells, block UV-induced AP-1 activation. The inhibition appears to be specific for UV-induced signal transduction for AP-1 activation, because these inhibitors did not block UV-induced p53 activation nor did they exhibit any significant inf luence on epidermal growth factor-induced AP-1 transactivation. Furthermore, the inhibition of UV-induced AP-1 activity occurs through a pathway that is independent of extracellular signalregulated kinases and c-Jun N-terminal kinases as well as P38 kinases. Considering the important role of AP-1 in tumor promotion, it is possible that blocking UV-induced AP-1 activity by Inh I or Inh II may be functionally linked to irradiation-induced cell transformation.Proteinase inhibitors I (Inh I) and II (Inh II) from potatoes are two well characterized inhibitors of chymotrypsin and trypsin (1, 2). Both inhibitors are heat-stable, Inh I having one disulfide bond and Inh II having six (1, 2). Both inhibitors are induced to accumulate in potato and tomato leaves in response to wounding and UV irradiation (3, 4), and have been shown to be involved with the induced defense response of plants against herbivores and pathogens (3). These inhibitors, as well as other plant proteinase inhibitors, have an inhibitory effect on x-irradiation-induced mammalian cell transformation (5), although the mechanism underlying their anticarcinogenic activity is not known. Because activator protein-1 (AP-1) is one of the most important transcription factors in the UV response in mammalian cells (6-8), we investigated the effects of Inh I and Inh II on UV-induced AP-1 transactivation. We report the both Inh I and Inh II block UV-induced AP-1 activity and that the induction is independent of extracellular signal-regulated kinases (Erks) and c-Jun N-terminal kinases (JNKs), as well as p38 kinase. MATERIALS AND METHODSPlasmids and Reagents. CMV-neu marker vector plasmid was constructed as reported (9); P53 luciferase reporter plasmid was the same as reported (10); fetal bovine serum (FBS), Lipofectamine, MEM, and G418 were from GIBCO͞BRL; epidermal growth factor (EGF) was from Collaborative Research; luciferase substrate was from Promega; the proteinase inhibitors I and II were isolated from potato tubers as described (1, 2). Inh I contains a reactive site that powerfully inhibits chymotrypsin, whereas Inh II is a ''double-headed'' inhibitor and strongly inhibits both trypsin and chymotrypsin; lima bean inhibitor (LBI) and soybean trypsin inhibitor (SBI) were purchased from Sigma.Generation of P53 Luciferase Reporter Stable Transfectant. JB6 cells, Cl 41, were cultured in six-well plates until they reached 85-90% confluence. ...

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Section: Resultsmentioning

confidence: 99%

Proteinase inhibitors I and II from potatoes specifically block UV-induced activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase

Huang

Ryan

et al. 1997

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

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“…Animal tests and medical experiments have shown that proteinase inhibitors of certain types are anticarcinogenic (Yavelow et al, 1983;Troll et al, 1987;Troll & Kennedy, 1989;Kennedy, 1994;Liener, 1995). The anticarcinogenic properties include the ability to reduce oxygen-radical formation (Yavelow et al, 1982;, to suppress the growth of chemical-induced colon and anal gland tumours in rats (Billings et al, 1990), breast tumours in rats and humans (Troll et al, 1980;Tamir et al, 1990) and lung tumours in mice (Witschi & Kennedy, 1989), to suppress chemical-or radiation-induced cell transformation (Billings et al, 1987(Billings et al, , 1989 and to reduce spontaneous chromosome abnormality (Afzal et al, 1989). Epidemiological studies suggest that human populations which are known to have high concentration of certain proteinase inhibitors, mainly Bowman±Birk and Kunitz families, in their diet have lower rates of colon, breast, prostate and skin cancers (Correa, 1981;Kennedy, 1998;Chen et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Crystallization and preliminary X-ray diffraction analysis of a novel trypsin inhibitor from seeds ofCopaifera langsdorffii

Krauchenco

Silva

Nagem

et al. 2001

Acta Crystallogr D Biol Cryst

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A novel trypsin inhibitor isolated from seeds of Copaifera langsdorffii was purified to homogeneity and crystallized. Crystals suitable for X-ray analysis were grown using the hanging-drop vapour-diffusion method at 291 K in sodium acetate buffer at pH values near 4.3 using PEG 4000 as precipitant. The crystals presented symmetry compatible with the space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = b = 58.71, c = 93.75 A, and diffracted to 1.83 A resolution at the synchrotron source.

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“…Gueven and coworkers [46] found a similar protective effect which was associated with the anti-chymotrypsin binding site of the protein. Other chymotrypsin inhibitors, including the chymotrypsin inhibitor I from potatoes, have been shown to be particularly effective in suppressing malignant transformation [47]. Because of the apparent association of the chymotrypsin inhibitory binding site with anti-carcinogenic properties, it has been hypothesised that chymotrypsin-like proteases are likely to be involved in carcinogenesis [48].…”

Section: Cancer Chemopreventive Propertiesmentioning

confidence: 99%

Biological Significance of Polymorphism in Legume Protease Inhibitors from the Bowman-Birk Family

Clemente¹,

Domoney

2006

CPPS

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Naturally occurring protease inhibitors (PI) of the Bowman-Birk type constitute a major PI family in cereal and legume seeds. The family name is derived from the names of the two investigators who characterised the first inhibitor of this type, the Bowman-Birk inhibitor from soybean (BBI). These proteins have the capacity to inhibit one or more of a range of serine proteases, including the digestive enzymes trypsin and chymotrypsin. PI from this family interact with the active sites of serine proteases in a 'canonical', i.e. substrate-like, manner via exposed reactive site loops of conserved conformation within the inhibitor. Multiple BBI variants can be found within and among species. A limited number of amino acids located within the inhibitory domain is responsible for the primary functional and biological activities of BBI-like proteins. However, sequence variation in binding loops, post-translational modifications at the amino- and carboxy-terminal ends, as well as differences in the multimeric nature of the inhibitors may act in combination to influence the functional properties and the physiological role of BBI-like proteins. Recently, BBI and proteins homologous to BBI (BBI-like proteins) have emerged as highly promising cancer chemopreventive agents. BBI has been shown to be capable of preventing or suppressing carcinogenic processes in a wide variety of in vitro and in vivo animal model systems. The potential exploitation of BBI-like proteins in human health-promotion programmes will depend on elucidating in detail the molecular basis for the variation in biological activities among the many variant forms. New knowledge, derived both from the use of synthetic cyclic peptides that mimic the inhibitory loops of BBI-like proteins, and from genomic data pertaining to the structure of BBI gene classes, together facilitate the manipulation, screening and selection of appropriate variants through biotechnology.

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Inhibition of radiation-induced transformation of C3H/10T½ cells by chymotrypsin inhibitor 1 from potatoes

Cited by 31 publications

References 0 publications

Proteinase inhibitors I and II from potatoes specifically block UV-induced activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase

Proteinase inhibitors I and II from potatoes specifically block UV-induced activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase

Crystallization and preliminary X-ray diffraction analysis of a novel trypsin inhibitor from seeds ofCopaifera langsdorffii

Biological Significance of Polymorphism in Legume Protease Inhibitors from the Bowman-Birk Family

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