Disease relevance of Odc1

• Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice [1].
• In early and large papillomas, staining for constitutively expressed ODC was intense and diffuse in suprabasal cells [2].
• In addition, in vivo inhibition of ODC with alpha-difluoromethylornithine also exacerbated the colitis [3].
• The current study evaluates the therapeutic effects of antisense ODC and AdoMetDC sequences on colorectal cancer in vitro and in vivo [4].
• Polyamine depletion by ODC-AdoMetDC antisense adenovirus impairs human colorectal cancer growth and invasion in vitro and in vivo [4].

Psychiatry related information on Odc1

• Dietary modification of UV-induced epidermal ornithine decarboxylase [5].
• The longer latency period, low incidence of tumor induction, low tumor yield and low induction of ODC activity as compared with TPA represent the weak but complete tumor promoting potential of in situ-generated ROS [6].

High impact information on Odc1

• We have previously shown that treatment of T lymphocytes with mitogenic ligands induces a rapid activation of ornithine decarboxylase (ODC) through a mechanism that is independent of protein synthesis but requires energy and an intact cytoskeleton [7].
• Growth signal transduction: rapid activation of covalently bound ornithine decarboxylase during phosphatidylinositol breakdown [7].
• Here we show by immunoprecipitation experiments and by chemical analyses that ODC is covalently linked to the cell membrane by inositol [7].
• These isolates were highly potent when evaluated for inhibition of chemically induced preneoplastic lesions in mammary organ culture and inhibition of papillomas in the two-stage mouse skin model, and they appear to function by a unique mechanism at the level of ODC messenger RNA expression [8].
• Using a cell-free degradation system, we demonstrate that immunodepletion of proteasomes from cell extracts causes almost complete loss of ATP- and antizyme-dependent degradation of ODC [9].

Chemical compound and disease context of Odc1

• Overexpression of antizyme in the hearts of transgenic mice prevents the isoprenaline-induced increase in cardiac ornithine decarboxylase activity and polyamines, but does not prevent cardiac hypertrophy [10].
• Administration of testosterone to female mice causes hypertrophy of their kidneys with spectacular induction of ornithine decarboxylase and significant increase in the level of putrescine [11].
• Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO) [12].
• Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA [13].
• Exposure of ornithine decarboxylase (ODC; L-ornithine carboxy-lyase, EC 4.1.1.17)-overproducing mouse FM3A cells to micromolar levels of spermine or spermidine caused abnormal accumulation and toxicity of polyamines [14].

Biological context of Odc1

• Finally, we show that the regulation of ODC stability by NQO1 is especially prominent under oxidative stress [15].
• The ODC gene contains a conserved repeat of the Myc binding site, CACGTG, in intron 1 [16].
• ODC-induced cell death was due to the induction of apoptosis [17].
• These results suggest that the expression of ODC or AdoMetDC may affect cell cycle regulation in many ways [18].
• Restoration of p27Kip1 expression in the ODC- and AdoMetDC-transformed cells by transfection resulted in growth inhibition, but not in morphological reversion [18].

Anatomical context of Odc1

• To assess this possibility, we first overexpressed ODC in the skin of Ptch1+/- mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle [1].
• In this report, we demonstrate that c-Myc is a potent transactivator of ODC promoter-reporter gene constructs in fibroblasts that requires the CACGTG repeat [16].
• 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 [2].
• Ornithine decarboxylase (ODC), which metabolizes L-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages [19].
• Nonetheless, ODC was required downstream of c-Myc for myeloid cell growth [20].

Associations of Odc1 with chemical compounds

• We further show that dicoumarol sensitizes ODC monomers to proteasomal degradation in an antizyme-independent manner [15].
• Furthermore, oral administration of the suicidal ODC inhibitor alpha-difluoromethylornithine reduced UVB-induced BCCs in Ptch1+/- mice [1].
• Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine [19].
• Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines [3].
• When treated with a single acute dose of isoprenaline (isoproterenol), cardiac ODC activity and putrescine content were substantially increased (by 14-fold and 4.7-fold respectively) in non-transgenic littermate mice, but these increases were completely prevented in the transgenic mice from both founder lines [10].

Physical interactions of Odc1

• Instead, ODC is targeted to degradation by direct binding to a polyamine-induced protein termed antizyme (Az) [21].
• Both an antennapedia-linked inhibitor of c-Myc binding (Int-H1-S6A,F8A) and transfection of a c-Myc dominant-negative construct significantly attenuated H. pylori-induced ODC promoter activity, mRNA, enzyme activity, and apoptosis in parallel [22].
• Bryostatin 1 decreased epidermal growth factor binding and induced ornithine decarboxylase activity, the latter a marker of proliferation [23].

Enzymatic interactions of Odc1

• Antizyme accelerated the degradations of both dephosphorylated ODC and native ODC [24].
• Due to the inability of the monoclonal antibody to recognize ornithine decarboxylase phosphorylated in vitro by casein kinase-II and the partial immunoprecipitation of ornithine decarboxylase activity from cell extracts, a portion of the ornithine decarboxylase molecule population must exist in a phosphorylated state [25].

Regulatory relationships of Odc1

• Our results demonstrate that AZ1 acts on ODC to enhance the association of ODC with the proteasome, not the rate of its processing [26].
• These sites conferred Myc responsiveness on heterologous promoter constructs, suggesting that ODC is regulated by Myc at the level of transcription initiation [16].
• These mice demonstrate for the first time that AZ suppresses tumor growth in an animal cancer model and provide a valuable model system to evaluate the role of ODC and polyamines in skin tumorigenesis [27].
• Treatment of B16 cells with TPA or alphaMSH rapidly stimulated ODC activity [28].
• A transgenic mouse line expressing a truncated form of the ornithine decarboxylase (ODC) dominant-negative mutant K69A/C360A under the control of the keratin 6 promoter has been established (K6/ODCdn mice) [29].

Other interactions of Odc1

• The 37 C-terminal amino acids of ODC harbor an AZ1-modulated recognition determinant [26].
• The ornithine decarboxylase gene is a transcriptional target of c-Myc [16].
• Enforced expression of ODC, like c-myc, is sufficient to induce accelerated death following IL-3 withdrawal [17].
• 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 [2].
• 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 [2].

Analytical, diagnostic and therapeutic context of Odc1

• The two transgenic lines had substantial, but different, levels of antizyme in the heart, as detected by Western blotting and by the ability of heart extracts to inhibit exogenous purified ODC [10].
• The DNA-binding activity of some transcription factors known to bind and transactivate the ODC gene was investigated by gel mobility-shift assay under the same experimental conditions [30].
• We studied changes in morphogenesis and the expression of the developmental control genes in the embryonic mouse kidney in response to polyamine depletion, using a kidney organ culture approach and reducing the polyamine pools with alpha-difluoromethylornithine (DFMO), an irreversible suicide inhibitor of ornithine decarboxylase (ODC) [31].
• The major degradation products of ODC, which were separated by high performance liquid chromatography on a reverse-phase column, were identified by N-terminal amino acid sequencing [32].
• Northern blot analysis revealed that the ODC mRNA level, that was increased 10-fold by testosterone, was decreased 2-fold in catecholamine-depleted hypertrophic kidney [33].

References