Anticarcinogenic Activity of Protease Inhibitors Overview

Kennedy, Ann R.

doi:10.1007/978-1-4615-2882-1_2

Cited by 67 publications

(36 citation statements)

References 118 publications

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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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“…These protease inhibitors are double-headed, with two reactive sites in a single inhibitor molecule. Interestingly, this type of inhibitor displays anticarcinogenic activity (Birk, 1993;Kennedy, 1993).The BBIs found in barley (Hordeum vulgare) and foxtail millet (Setaria italica) are either 8-or 16-kD proteins (Nagasue et al, 1988;Tashiro et al, 1990). The three-dimensional structures of the 8-and 16-kD BBIs have been explored (Li de la Sierra et al, 1999;Song et al, 1999).…”

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confidence: 99%

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confidence: 99%

Molecular Cloning and Functional Analysis of a Novel Type of Bowman-Birk Inhibitor Gene Family in Rice

et al. 2003

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inhibitor (BBI) genes encode serine protease inhibitors that have repetitive cysteine-rich domains with reactive sites for the trypsin or chymotrypsin family. We have identified seven BBI genes from japonica rice (Oryza sativa subsp. japonica var Teqing). All of the genes identified were found in a single cluster on the southern end of the long arm of rice chromosome 1. Four of the seven BBI genes have two repetitive cysteine-rich domains, whereas one has a truncated domain with only one reactive site. We have also identified three novel BBI genes, each of which possesses three repetitive domains instead of two. In situ hybridization analyses indicated that the accumulation of rice BBI transcripts was differentially regulated in germinating embryos and also in the leaves, roots, and flower organs at later developmental stages. Different members of the rice BBI gene family displayed different expression patterns during rice seed germination, and wounding induced the expression of rice BBI transcripts. The three-domain BBIs had higher expression levels than the two-domain BBIs. It was also found that the mRNA of rice BBI genes was present in abundant amounts in scutellar epithelium and aleurone layer cells. RBBI3-1, one of the three-domain RBBI, exhibited in vitro trypsin-inhibiting activity but no chymotrypsin-inhibiting activity. Overexpression of RBBI2-3 in transgenic rice plants resulted in resistance to the fungal pathogen Pyricularia oryzae, indicating that proteinase inhibitors confer resistance against the fungal pathogen in vivo and that they might play a role in the defense system of the rice plant.Plants have developed defense systems to combat various pathogens throughout their life cycle, from the seed stage until senescence, and it is particularly important that the embryo be kept free from infection. There are several embryonic defense mechanisms, including the production of plant lectins and pathogen-related proteins in response to attacks by pathogens or insects (Swegle et al., 1992;Ye et al., 2001;Guiderdoni et al., 2002). A well-known defense component is Ser protease inhibitors. They are expressed in developing seeds and are thought to play an important role in inhibiting trypsin and chymotrypsin of external origin (Ryan, 1981). Two major Ser protease inhibitors have been studied extensively in plants: Kunitz inhibitors and Bowman-Birk inhibitors (BBIs; Ryan, 1990). BBIs are Cys-rich proteins of about 8 to 16 kD with disulfide bonds and are encoded by a family of related genes. The BBI gene family has been found in both the Fabaceae and the Poaceae. BBIs identified in Fabaceae, such as soybean (Glycine max) and lima bean (Phaseolus lunatus), are 8-kD proteins. They have one BBI domain with two reactive sites for trypsin and the related enzymes, such as chymotrypsin (Birk, 1987). These protease inhibitors are double-headed, with two reactive sites in a single inhibitor molecule. Interestingly, this type of inhibitor displays anticarcinogenic activity (Birk, 1993;Kennedy, 1993).The BBIs found in...

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“…In contrast to ovomucin, cystatin is a small molecule (12.7 kDa) and it has no carbohydrates and a high thermal stability. The potential of their broad application in medical treatments has been reported in the literature, which includes antimicrobial and antiviral activities [83], the prevention of cerebral hemorrhage [84] and control of cancer cell metastasis [85].…”

Section: Cystatinmentioning

confidence: 99%