Disease relevance of Oaz1

• K6-AZ(18) and K5-AZ mice also developed fewer papillomas than littermate controls (35% and 50%, respectively), and the combination of these lines to produce double transgenic animals yielded an additive decrease (70%) in tumor multiplicity [1].
• Northern blot analysis shows that although high concentrations of polyamines do not affect the steady-state levels of antizyme message in L1210 leukemia cells, polyamine depletion using 2-(difluoromethyl)ornithine [Orn(F2Me)] leads to a marked decrease in mRNA levels [2].
• 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 [3].
• Antizyme protects against abnormal accumulation and toxicity of polyamines in ornithine decarboxylase-overproducing cells [4].
• Recombinant antizyme protein was also produced in Escherichia coli and used to raise specific polyclonal antibodies in rabbits and to devise immunological methods for the measurement of antizyme concentration [5].

High impact information on Oaz1

• Rat antizyme gene expression requires programmed, ribosomal frameshifting [6].
• 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 [7].
• ODC is a homodimeric enzyme that undergoes ubiquitin-independent proteasomal degradation via direct interaction with antizyme, a polyamine-induced protein [8].
• We further show that dicoumarol sensitizes ODC monomers to proteasomal degradation in an antizyme-independent manner [8].
• Ptch1+/- mice with AZ overexpression driven by the K6 promoter were resistant to the induction of BCCs by UVB [9].

Biological context of Oaz1

• Discovery of a spermatogenesis stage-specific ornithine decarboxylase antizyme: antizyme 3 [10].
• Antizyme 3 cDNA has the same arrangement of reading frames and a potential shift site with definite, although limited, homology to its evolutionarily distant antizyme 1 and 2 counterparts [10].
• As polyamines are involved in maintaining cellular proliferation, and since AzI may negate Az functions, we have investigated the role of AzI in regulating cell growth [11].
• Antizyme inhibitor retains no enzymatic activity, but exhibits high affinity to antizyme (Az), a negative regulator of polyamine homeostasis [11].
• By causing ribosomal frameshifting, polyamines induce the synthesis of antizyme, a 23-kDa protein, which binds to ODC, inhibits its activity and promotes its degradation by the 26 S proteasome [12].

Anatomical context of Oaz1

• Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions [11].
• Interestingly, we found that cultivation of mandibular components of the first branchial arch in the presence of a selective proteasome inhibitor caused ODC accumulation in the nucleus of a subset of cells, suggesting that the observed nuclear translocation of AZ is linked to proteasome-mediated ODC degradation in the nucleus [13].
• In contrast with previous studies demonstrating stability in vitro in a reticulocyte lysate-based degradation system, in cells antizyme is rapidly degraded and this degradation is inhibited by specific proteasome inhibitors [14].
• Results of transient transfections of luciferase-reporter-gene constructs driven by antizyme promoter fragments in untreated and Orn(F2Me)-treated Balb/C 3T3 cells indicate that the transcription of the antizyme gene is altered upon polyamine depletion [2].
• Inducible antizyme largely enters mitochondria resulting in cytochrome c release from mitochondria to cytosol following Bcl-xL decrease and Bax increase [15].

Associations of Oaz1 with chemical compounds

• Antizyme, a protein inhibitor of ornithine decarboxylase (ODC), was shown to be induced in mouse kidney by repeated injection of putrescine [16].
• On the contrary, the proportion of ODC present as a complex with antizyme was 24-fold higher in females than in males, and the decay of renal ODC activity after cycloheximide treatment was about 5-fold more rapid in females than in males [16].
• Testosterone treatment enhanced AZ1 and N1-SSAT mRNA levels in a time-dependent manner by unknown molecular mechanisms [17].
• Further, ODC enzyme activity, which is influenced by both ODC and AZ RNA levels and inhibited by DFMO, is consequential for small intestinal tumorigenesis in this model [18].
• When peptide 119-144 or peptide 211-216, which are responsible for the binding of ODC, were deleted from antizyme, the mutant antizyme could not reverse the inhibition of growth of EXOD-1 cells produced by spermine [19].

Physical interactions of Oaz1

• Instead, ODC is targeted to degradation by direct binding to a polyamine-induced protein termed antizyme (Az) [20].
• Moreover, Az binding actually stabilizes AzI by inhibiting its ubiquitination [20].

Enzymatic interactions of Oaz1

• Antizyme accelerated the degradations of both dephosphorylated ODC and native ODC [21].

Regulatory relationships of Oaz1

• 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 [1].
• Our results suggest opposing roles of Az in regulating the degradation of AzI and ODC [20].
• The degradation of both antizyme proteins is inhibited in ts20 cells containing a thermosensitive ubiquitin-activating enzyme, E1 [14].

Other interactions of Oaz1

• Targeted antizyme expression in the skin of transgenic mice reduces tumor promoter induction of ornithine decarboxylase and decreases sensitivity to chemical carcinogenesis [1].
• Antizyme, in turn, is inhibited by antizyme inhibitor (AZI) [12].
• The expression of AZ1 and N1-SSAT mRNA was similar in male and female mouse kidneys [17].
• The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 12)-transformed NIH3T3 cells and several human malignant cell lines including a line with loss of p53 expression, and they were shown to be as sensitive as nontransformed NIH3T3 cells in vitro [22].
• The in vivo anti-tumor activity was also tested using nude mice inoculated with H-ras transformed NIH3T3 cells that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice [22].

Analytical, diagnostic and therapeutic context of Oaz1

• The amount of antizyme protein on Western blots was also altered by polyamine depletion and addition, and the polysomal distribution of antizyme message suggests a general translational increase of the message when polyamine concentrations are high [2].
• Although effects of AZ on functions other than polyamine metabolism are possible, alterations in polyamines are the most likely explanation for the reduction in tumors, supporting the use of strategies to modulate polyamine levels for cancer chemoprevention in individuals at high risk of developing malignancies of the gastrointestinal tract [23].
• The hamster ODC-Az gene demonstrated a restriction fragment length polymorphism (RFLP) upon Southern blot analysis comparing normal and tumor hamster genomic DNA [24].
• Putrescine concentrations start to increase 8 h after treatment with allylglycine and concomitantly with this increase, antizyme is released to inhibit enzyme activity [25].
• In addition to ODC-antizyme complex, inactive ODC protein was detected by radioimmunoassay in about the same level as the complex at 3 weeks of age [26].

References