Identification of Differentially Expressed Genes in Normal and Tumor Human Gastric Tissue

Jung, Myeong Ho; Kim, Sung Chun; Jeon, Geoung A; Kim, Seung Hyun; Kim, Youngyul; Choi, Kyoung Hwa; Park, Sang Ick; Margetis, Joe; Kimm, Kuchan

doi:10.1006/geno.2000.6338

Cited by 83 publications

(65 citation statements)

References 29 publications

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“…Downregulation of antizyme inhibitor activity is associated with reduced cell proliferation (Choi et al, 2005;Kim et al, 2006). Moreover, overexpression of AZI increases cell proliferation and promotes cell transformation (Keren-Paz et al, 2006;Kim et al, 2006) and high levels of AZI have been observed in gastric tumors (Jung et al, 2000). Our results show that overexpression of AZI induces aberrant synthesis of daughter centrioles as reported previously for the papillomavirus-16 E7 oncoprotein (Guarguaglini et al, 2005).…”

Section: Discussionsupporting

confidence: 84%

“…AZI is highly homologous to ODC but lacks its enzymatic activity (Murakami et al, 1996). Reduced AZI expression leads to inhibition of cell proliferation (Choi et al, 2005;Kim et al, 2006) and recent data suggest a possible correlation between AZI and malignancy (Jung et al, 2000;Keren-Paz et al, 2006;Kim et al, 2006). In summary, antizyme 1 and AZI act together to regulate ubiquitin-independent degradation of proteins that modulate polyamine metabolism and cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

et al. 2007

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The potential tumor suppressor antizyme and its endogenous inhibitor (antizyme inhibitor, AZI) have been implicated in the ubiquitin-independent proteasomal degradation of proteins involved in cell proliferation as well as in the regulation of polyamine levels. We show here that both antizyme and AZI concentrate at centrosomes and that antizyme preferentially associates with the maternal centriole. Interestingly, alterations in the levels of these proteins have opposing effects on centrosomes. Depletion of antizyme in various cell lines and primary cells leads to centrosome overduplication, whereas overexpression of antizyme reduces numerical centrosome abnormalities. Conversely, silencing of the antizyme inhibitor, AZI, results in a decrease of numerical centrosome abnormalities, whereas overexpression of AZI leads to centrosome overduplication. We further show that the numerical centrosome abnormalities are due to daughter centriole amplification. In summary, our results demonstrate that alterations in the antizyme/AZI balance cause numerical centrosomal defects and suggest a role for ubiquitin-independent proteasomal degradation in centrosome duplication.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

et al. 2007

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“…It was shown that in some cases the increased ODC activity is a direct result of elevated ODC expression (Nilsson et al, 2005). On the other hand, based on our present results and on a recent observation demonstrating increased levels of AzI mRNA in gastric tumors (Jung et al, 2000), we propose here that augmented levels of ODC can be caused by its stabilization due to elevated AzI expression that neutralizes Az functions (Figure 7). More importantly, as we show here, overexpressed AzI also increases polyamine uptake, resulting in accumulation of spermidine and spermine.…”

Section: Discussionsupporting

confidence: 78%

“…Human AzI gene is located on chromosome 8q22.3, and amplification of this region were found in several tumors (Schaner et al, 2005;van Duin et al, 2005). In agreement with this hypothesis are recent findings demonstrating AzI overexpression in gastric tumors (Jung et al, 2000), and decreased intracellular polyamine levels and reduced cell proliferation in cells with downregulated AzI expression (Choi et al, 2005).…”

Section: Introductionsupporting

confidence: 54%

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions

et al. 2006

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Antizyme inhibitor (AzI) is a homolog of ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis. Antizyme inhibitor retains no enzymatic activity, but exhibits high affinity to antizyme (Az), a negative regulator of polyamine homeostasis. 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. We show here that overexpression of AzI in NIH3T3 cells increased growth rate, enabled growth in low serum, and permitted anchorage-independent growth in soft agar, while reduction of AzI levels by AzI siRNA reduced cellular proliferation. Moreover, AzI overproducing cells gave rise to tumors when injected into nude mice. AzI overexpression resulted in elevation of ODC activity and of polyamine uptake. These effects of AzI are a result of its ability to neutralize Az, as overexpression of an AzI mutant with reduced Az binding failed to alter cellular polyamine metabolism and growth properties. We also demonstrate upregulation of AzI in Ras transformed cells, suggesting its relevance to some naturally occurring transformations. Finally, increased uptake activity rendered AzI overproducing and Ras-transformed cells more sensitive to toxic polyamine analogs. Our results therefore imply that AzI has a central and meaningful role in modulation of polyamine homeostasis, and in regulating cellular proliferation and transformation properties.

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“…Transgenic mice overexpressing AZ showed reduced tumorigenesis (32,33), and AZI has been found to be elevated in some tumors (34) and stimulated by growth-promoting stimuli (35). Recent reports have revealed that AZ may also interact with proteins other than ODC, related with signal transduction such as Smad-1 (36) or cell cycle progression such as cyclin D1 (37), increasing the interest on the potential role of these ODC-related proteins in the control of cell growth.…”

mentioning

confidence: 99%

Mouse Ornithine Decarboxylase-like Gene Encodes an Antizyme Inhibitor Devoid of Ornithine and Arginine Decarboxylating Activity

López-Contreras

López‐García

Jiménez‐Cervantes

et al. 2006

Journal of Biological Chemistry

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Ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, is a labile protein that is regulated by interacting with antizymes (AZs), a family of polyamine-induced proteins. Recently, a novel human gene highly homologous to ODC, termed ODC-like or ODC-paralogue (ODCp), was cloned, but the studies aimed to determine its function rendered contradictory results. We have cloned the mouse orthologue of human ODCp and studied its expression and possible function. mRNA of mouse Odcp was found in the brain and testes, showing a conserved expression pattern with regard to the human gene. Transfection of mouse Odcp in HEK 293T cells elicited an increase in ODC activity, but no signs of arginine decarboxylase activity were evident. On the other hand, whereas the ODCp protein was mainly localized in the mitochondrial/membrane fraction, ODC activity was found in the cytosolic fraction and was markedly decreased by small interfering RNA against human ODC. Co-transfection experiments with combinations of Odc, Az1, Az2, Az3, antizyme inhibitor (Azi), and Odcp genes showed that ODCp mimics the action of AZI, rescuing ODC from the effects of AZs and prevented ODC degradation by the proteasome. A direct interaction between ODCp and AZs was detected by immunoprecipitation experiments. We conclude that mouse ODCp has no intrinsic decarboxylase activity, but it acts as a novel antizyme inhibitory protein (AZI2).The polyamines spermidine and spermine and their precursor putrescine are ubiquitous polycations implicated in the growth, differentiation, and death of eukaryotic cells (1-4). Intracellular levels of polyamines are tightly regulated through multiple mechanisms affecting their biosynthesis, catabolism, and transport (5-9). In mammalian cells, putrescine synthesis, the first step in the polyamine biosynthetic pathway, is mediated by ornithine decarboxylase (ODC) 2 (EC 4.1.1.17) through the decarboxylation of L-ornithine. This enzyme is subject to a complex regulation by transcriptional, translational, and posttranslational mechanisms (10 -16). At the post-translational level, ODC is finely regulated by a family of inhibitory proteins called antizymes (AZ) (15,17,18). AZ1, the first described member of the family, binds to ODC monomers preventing the formation of active ODC homodimers and promoting the degradation of ODC through the 26 S proteasome in a ubiquitinindependent manner (19 -21). Synthesis of AZ is influenced by polyamines through the stimulation of ribosomal frameshifting (22,23). Moreover, the action of AZ on ODC function is also mediated by a protein called antizyme inhibitor (AZI). This protein, having a sequence highly similar to that of ODC, is devoid of ornithine decarboxylating activity; however, it can activate ODC by competing for AZ, because AZI binds to AZ with high affinity preventing or decreasing the formation of the ODC-AZ complex (24, 25). In addition, AZ1 and AZ2 not only decrease polyamine biosynthesis but also prevent the accumulation of excess polyamines by inhibiting or suppre...

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Identification of Differentially Expressed Genes in Normal and Tumor Human Gastric Tissue

Cited by 83 publications

References 29 publications

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions

Mouse Ornithine Decarboxylase-like Gene Encodes an Antizyme Inhibitor Devoid of Ornithine and Arginine Decarboxylating Activity

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