Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.17 (ornithine decarboxylase)
6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous experiments, pretreatment of CD-1 mouse skin with prostratin (12-deoxyphorbol 13-acetate) inhibited hyperplasia, induction of ornithine decarboxylase and edema in response to acute treatment with phorbol 12-myristate 13-acetate (PMA). We report here that prostratin inhibits biological responses induced by multiple (chronic) PMA treatment. A typical chronic treatment schedule consisted of five applications of 3.2 nmol (2 micrograms) PMA at 48 h intervals. Most effective inhibition could be achieved when the first PMA treatment was preceded 48 h before by a lower dose of prostratin (256 nmol = 100 micrograms) and each PMA treatment was preceded 15 min before by a higher dose (2.56 mumol = 1 mg) of prostratin. Under this schedule hyperplasia was completely blocked, as was keratin K6 expression (a marker of hyperproliferative epidermis), whereas myeloperoxidase activity (a marker of neutrophil granulocyte infiltration) was reduced to 36%. 12-Deoxyphorbol 13-phenylacetate (dPP), a non-promoting 12-deoxyphorbol derivative that binds to protein kinase C with two orders of magnitude higher potency than does prostratin, showed the same pattern of inhibition as did prostratin for a single PMA treatment but with a corresponding two orders of magnitude higher potency. In the case of chronic PMA treatment, however, dPP failed to inhibit hyperplasia fully, though it reduced keratin K6 expression and inflammation. Dissociation of K6 expression from hyperplasia was unexpected, since expression of these two responses was thought to be closely coupled. We conclude that 12-deoxyphorbol 13-monoesters are functional antagonists for a class of protein kinase C-mediated responses closely correlated to tumor promotion.
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PMID:Non-promoting 12-deoxyphorbol 13-esters as potent inhibitors of phorbol 12-myristate 13-acetate-induced acute and chronic biological responses in CD-1 mouse skin. 138 2

Butylated hydroxytoluene (BHT) and certain carotenoid pigments have been found to inhibit photocarcinogenesis in animal models. In addition, BHT protects against UV-B-induced erythema and UV-B induction of ornithine decarboxylase. Studies on the photoprotective mechanism(s) of BHT suggested that changes in the physico-chemical properties of the keratin of the stratum corneum layer of skin occurred, leading to increases in UV absorption of that tissue. These changes might be exerted via the anti-radical action of BHT that retards oxidation and prevents cross-linking of the keratin chains, resulting in a diminution of UV-B radiation reaching potential target sites. The carotenoids beta-carotene, canthaxanthin and phytoene also inhibit UV-B carcinogenesis. beta-Carotene and canthaxanthin are excellent quenchers of singlet oxygen, and all three pigments can quench free radicals. beta-Carotene and canthaxanthin have been shown to quench singlet oxygen/free radical reactions in the skin of porphyric mice, and these two pigments as well as phytoene have been found to quench excited species formed on irradiation of mouse skin by UV-B.
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PMID:Protective role of butylated hydroxytoluene and certain carotenoids in photocarcinogenesis. 188 65

The expression of epidermal growth factor receptor and transglutaminase type I, polyamine (putrescine, spermidine, and spermine) levels, ornithine decarboxylase activity, and micronuclei occurrence were assessed in the 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch model to elucidate the role and timing of changes in different growth and differentiation markers during carcinogenesis. DMBA (0.5%) in heavy mineral oil was applied to the right buccal pouch 3 times per wk for up to 16 wk; controls received heavy mineral oil alone. Hamsters were killed after 0, 4, 8, and 16 wk. Frozen tissue was chemically analyzed for polyamine levels and ornithine decarboxylase activity and was also used for immunohistochemical analysis of transglutaminase I. Paraffin-embedded sections were used for epidermal growth factor receptor immunohistochemical determinations and for micronucleated cell assays. Hyperplasia was detected by histological analysis at 4 wk, dysplasia with or without papillomatous changes at 8 wk, and squamous cell carcinoma at 16 wk. Epidermal growth factor receptor was not expressed in the normal buccal epithelial layer, at a moderate level in both the superficial keratin and basal cell layers in hyperplastic epithelium, and at very high levels in both dysplasia and squamous cell carcinoma. Transglutaminase I was expressed at a limited level in normal buccal mucosa, was expressed at a low level in the basal layer of hyperplastic lesions, was somewhat elevated in dysplasia, and was markedly enhanced in squamous cell carcinoma. Putrescine and spermidine levels and ornithine decarboxylase activity increased dramatically after 8 and 16 wk of DMBA. Micronucleated cells increased after 4 wk of DMBA treatment, that high level sustained during all stages of carcinogenesis. We suggest that these biological markers could be excellent intermediate end points in assessing the effects of various chemopreventive agents to be tested in the hamster buccal pouch model and in human clinical trials.
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PMID:Expression of epidermal growth factor receptor, polyamine levels, ornithine decarboxylase activity, micronuclei, and transglutaminase I in a 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model. 196 30

Retinol circulates in the plasma bound to retinol-binding protein (RBP), but the mechanism by which retinol is transferred from RBP to target cells is not known. To study retinol delivery, human keratinocytes (HKc) were incubated with [3H]retinol added directly to the culture medium or bound to RBP and the uptake of [3H]retinol was determined at various times. During the first hour of incubation, the rate of [3H]retinol accumulation by HKc was about 40 times greater when the vitamin was added directly to the media rather than bound to RBP. Although maximal uptake of [3H]retinol added directly to the culture medium occurred at 3 h, the uptake of [3H]retinol from RBP was linear with time for at least 72 h. By 57 h, cell-associated [3H]retinol was the same whether it was added directly to the culture medium or bound to RBP. Excess unlabeled retinol or pretreatment of HKc with retinol had no effect on the uptake of [3H]retinol added directly to the culture medium or bound to RBP. Apo- but not holo-RBP was capable of competing with HKc for the uptake of [3H]retinol from RBP. No specific or saturable binding of 125I-labeled RBP to HKc cultured in the absence or the presence of retinol was found. The dose response of retinol inhibition of cholesterol sulfate synthesis and phorbol ester-induced ornithine decarboxylase activity or retinol modulation of keratin expression was the same whether the retinol was delivered to HKc bound to RBP or added directly to the medium. Our data support a mechanism for retinol delivery from RBP to HKc that does not involve cell-surface RBP receptors but instead suggest that the vitamin is first slowly released from RBP and then becomes cell-associated from the aqueous phase. This mechanism is consistent with the finding that HKc respond identically to retinol whether or not it is delivered to them bound to RBP.
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PMID:Comparison of the rate of uptake and biologic effects of retinol added to human keratinocytes either directly to the culture medium or bound to serum retinol-binding protein. 132 1

As compared with the adult state, neonatal mouse skin (strain NMRI) has a hyperplastic appearance which gradually changes into the mature type between postnatal day 3 and 10. Concomitantly, the late fetal and neonatal keratin polypeptide pattern is replaced by the mature pattern. As long as the adult type of epidermal differentiation is not sufficiently developed (i.e., prior to postnatal day 5), topical application of the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) causes neither morphological alterations nor a measurable induction of cellular proliferation and ornithine decarboxylase activity. TPA application at day 7 evokes, however, (i) a hyperplastic reaction followed by a massive 'psoriasis-like' hyperkeratosis, (ii) an increase of ornithine decarboxylase activity and (iii) a restoration of the neonatal keratin polypeptide pattern. Multistage tumorigenesis experiments carried out with prenatally initiated mice show that during the early period of development (prior to postnatal day 5) mouse skin is also resistant to the effects of TPA as a stage I tumor promoter. Since both the hyperplastic response and the sensitivity to tumor promotion develops in a strictly parallel manner, reactions involved in the induction of epidermal hyperplasia are assumed to provide an important condition of stage I skin tumor promotion.
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PMID:Development of phorbol ester responsiveness in neonatal mouse epidermis: correlation between hyperplastic response and sensitivity to first-stage tumor promotion. 257 99

Murine embryonal carcinoma F9 cells can be induced to differentiate by 2-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC). The differentiated phenotype is similar to that of retinoic acid (RA)-treated F9 cells. In contrast to F9 cells the differentiated cells secrete plasminogen activator and express keratin intermediate filaments. Both DFMO and RA reduce ornithine decarboxylase activity, polyamine levels and inhibit cell proliferation of F9 cells. These compounds also reduce ODC, polyamine levels and proliferation of mouse BALB/c 3T6 fibroblasts. RA inhibits the induction of ODC by insulin, serum and to a lesser extent that of epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The action of DFMO and RA can be distinguished by their response to putrescine. The induction of differentiation and the inhibition of cell proliferation by DFMO can be totally abolished upon the addition of putrescine, whereas the actions of RA are not affected at all. These results suggest that the inhibition of ODC and reduction of polyamines are not causal in the induction of differentiation and the inhibition of proliferation by RA.
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PMID:Inhibition of ornithine decarboxylase by retinoic acid and difluoromethylornithine in relation to their effects on differentiation and proliferation. 391

It is possible to evaluate different dermatological therapeutic agents intended for human use in a variety of animal assays. This review will discuss some of these assays, and attempt to correlate animal and human skin responses. Psoriasis is a disease where changes in epidermal proliferation may be an important factor. It is possible to assay potential anti-psoriatic agents by measuring their ability to suppress DNA synthesis in the epidermis of hairless mice. This assay is predictive of the anti-psoriatic effectiveness of numerous agents including a variety of anti-proliferative drugs and anthralin, and has been used to evaluate the potential efficacy of purified coal tar shampoos and body preparations. The activity of the polyamine biosynthesis enzyme ornithine decarboxylase (ODC) is elevated in psoriatic skin, and it is induced in mouse epidermis by tape stripping. Retinoids can inhibit the induction of ODC activity, and this inhibition may be used to evaluate novel synthetic retinoids. Retinoids have beneficial effects on the abnormal keratinization found in various diseases. Rhino mice have multiple keratin-filled epidermal utricles, and the size of these is reduced by retinoid treatment. Observing the changes in the size of the utricles can be utilized to evaluate the effects of retinoids on keratinization. Sunscreen agents are tested on human volunteers by observing their ability to inhibit the erythema induced by exposure to solar-simulated light, to obtain a sun protection factor (SPF). It is possible to utilize the ability of sunscreens to inhibit other actinic-induced changes in the skin using animals. Parameters that may be measured include changes in DNA synthesis and ODC activity in the epidermis following ultraviolet irradiation. Some of these assays correlate well with human SPF determinations.
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PMID:Animal assays for anti-psoriatic, retinoid and sun protective agents. 637 47

Studies of tumor induction on mouse skin have provided insight into the basis biology of chemical carcinogenesis, but molecular mechanisms have been more difficult to elucidate. Mouse epidermal cell cultures have proven to be a valuable model for performing mechanistic studies. Previous data have indicated that such cultures proliferate and differentiate in a manner highly analogous to epidermis in vivo. In addition, carcinogen metabolism, DNA repair, and responses to tumor promoters are quite similar in mouse skin in vivo and in vitro. Recent data have extended these observations toward defining the biological characteristics of initiated cells and elucidating the mechanism of action of promoters and antipromoters. When mouse epidermis is cultured under conditions of low extracellular Ca++, proliferation is enhanced and terminal differentiation is inhibited. Addition of Ca++ induces terminal differentiation. If cells are treated with carcinogens under low Ca++ conditions and subsequently switched to standard Ca++, cell colonies which do not terminally differentiate evolve. Such colonies continue to synthesize keratin, are subculturable, and may represent preneoplastic cells. In other experiments, epidermal cells derived from mouse skin treated with carcinogens in vivo also demonstrate prolonged in vitro survival and subculturability while controls have a limited lifespan. Such studies suggest that biological alterations can be detected in epidermal cells exposed to carcinogens well before and the phenotypic expression of neoplasia. Exposure of epidermal cells to phorbol-ester tumor promoters induces ornithine decarboxylase (ODC). This induction is enhanced by corticosteroids and markedly inhibited by retinoids. Ultraviolet light also induces ODC in epidermal cells, but kinetic studies suggest that the early pathway of induction (afferent to the nucleus) is different from that of phorbol esters. The later pathways (efferent from the nucleus-i.e., transcription and translation) appear to be similar. Retinoids have only a minor suppressive effect on ODC induction by UV while corticosteroids enhance UV induction to the same extent as seen with phorbol esters These results suggest that the site of retinoids is in the afferent pathway while steroids act on the efferent pathway.
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PMID:Chemical carcinogenesis studies in mouse epidermal cell cultures. 723 91

Primary mouse epidermal cells underwent spontaneous malignant transformation in culture. TWelve malignant epidermal cell lines were established which produced squamous cell carcinomas in syngeneic hosts. These lines were used to define criteria for recognizing transformed epidermal cells in vitro. Growth in suspension in agar, agarose, or Methocel was minimal for 11 of the lines. All lines tested retained specific epidermal antigens (pemphigus, pemphigoid, keratin) by indirect immunofluorescence, but keratin content was reduced when quantified by radioimmunoassay. Basal activity of ornithine decarboxylase and activity induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate were variable among lines. All malignant lines as well as normal epidermal cells grew well at reduced extracellular calcium concentrations. When the extracellular calcium was elevated, normal cells ceased proliferation, terminally differentiated, and sloughed from the culture dish, while malignant cells continued to proliferate although they expressed differentiative functions. These results indicate that malignant transformation in epidermis is associated with a fundamental alteration in the program of terminal differentiation which allows some cells to escape the proliferative block and cell death which accompanies differentiation in normal keratinocytes. This alteration should be useful to select for transformants during the process of carcinogenesis in vitro.
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PMID:A survey of transformation markers in differentiating epidermal cell lines in culture. 743 1

The patterns of expression of ornithine decarboxylase (ODC) and a number of keratinocyte differentiation products were examined in early papillomas by immunocytochemistry as an initial effort to develop phenotypic markers of the early stages of mouse skin tumorigenesis. Tumors were induced in SENCAR mice by initiation with 7,12-dimethylbenzanthracene, followed by once or twice weekly promotion treatments with 12-O-tetradecanoylphorbol-13-acetate. The patterns of immunocytochemical staining observed in early papillomas, collected after 7 weeks of promotion, were compared to those obtained with control skin and large, hyperkeratotic papillomas, collected after 23 weeks of promotion. In groups receiving 12-O-tetradecanoylphorbol-13-acetate, constitutive and induced ODC expression were evaluated either several days or 4.5 h after the last treatment, respectively. The major differentiation products in suprabasal keratinocytes are keratins, K1 and K10. These keratins were normally expressed in mildly hyperplastic epidermis, but staining became patchy in markedly hyperplastic epidermis. In early papillomas, K1 staining was patchy, and K10 staining occurred in very limited focal areas or was negative, such that the absence of staining delineated the lesions. Antibodies to the basal cell keratins, K5 and K14, stained both basal and suprabasal cells in hyperplastic epidermis and papillomas. Similarly, an antibody to keratin K6, which is expressed under conditions of hyperproliferation, uniformly stained the basal and suprabasal layers of hyperplastic epidermis and papillomas, demonstrating that the staining patterns observed with the antibodies to K1 and K10 were specific. Expression of ODC in the histologically normal skin of control mice was detected only in the hair follicles and depended on the hair cycle. Staining for induced ODC in mice treated with 12-O-tetradecanoylphorbol-13-acetate once weekly for 7 weeks was intense and diffuse throughout the suprabasal layers of the epidermis. In early and large papillomas, staining for constitutively expressed ODC was intense and diffuse in suprabasal cells. This intense staining for ODC occurred consistently in areas with decreased K1 and K10 expression, and, therefore, was associated with an altered pattern of differentiation. High constitutive ODC expression and decreased K1 and K10 expression will be useful phenotypic markers for studying the early stages of tumorigenesis in mouse skin.
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PMID:Ornithine decarboxylase expression in cutaneous papillomas in SENCAR mice is associated with altered expression of keratins 1 and 10. 750 17


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