Intracellular Localization of Ornithine Decarboxylase and Its Regulatory Protein, Antizyme-1

Schipper, Raymond G.; Cuijpers, Vincent M.J.I.; Groot, Linda H.J.M. de; Thio, Marco; Verhofstad, A.A.J.

doi:10.1177/002215540405201002

Cited by 34 publications

(13 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The previous report showed that AZ1 is primarily localized in the nucleus where it transports ODC from the cytosol for degradation by nuclear proteasome (Gritli-Linde et al 2001, Murai et al 2003, Schipper et al 2004. By contrast, we found that AZ1 was mainly localized in the cytosol during conversion of AsPC-1 cells to the differentiated state (Fig.…”

Section: J-i Suzuki Et Al: Glucagon-producing Cell Differentiationcontrasting

confidence: 45%

Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells

Suzuki¹,

Murakami²,

Samejima³

et al. 2009

Endocrine-Related Cancer

View full text Add to dashboard Cite

Human pancreatic tumor cell lines -AsPC-1, PANC-1, MIA paca2, KP-1 and KP-59 cellscan be induced to differentiate into pancreatic hormone-producing cells by brief trypsin treatment and subsequent culture in a serum-free, chemically defined medium. During culture, AsPC-1 cells formed cell clusters resembling the pancreatic islets, expressed genes associated with the pancreatic development and produced glucagon but not insulin. When PANC-1, MIA paca2, KP-1 and KP-59 cells were treated and cultured the same way, they underwent similar morphological changes and produced insulin and glucagon. We used these systems to identify intracellular regulatory molecules involved in the conversion of pancreatic tumor cells into glucagon-producing cells. We found that the expression of antizyme 1 (AZ1), a negative regulator of ornithine decarboxylase, was increased and its localization was altered from the nucleus to the cytoplasm during AsPC-1 cell differentiation. Transient transfection of AsPC-1 cells with AZ1 siRNA resulted in inhibition of the morphological and functional cell differentiation as well as the specific suppression of AZ1 expression. By contrast, constitutive overexpression of AZ1 in AsPC-1 cells led to the enhancement of glucagon production. We also found that PANC-1 cells reduced the expression of glucagon mRNA when treated with AZ1 siRNA. These results suggested that AZ1 was necessary for the conversion of pancreatic tumor cells into glucagon-producing cells. Glucagon production in AsPC-1 cells was not affected by addition of putrescine, suggesting that the polyamines were not directly involved in the AZ1-mediated conversion of pancreatic tumor cells to differentiated state.

show abstract

Section: J-i Suzuki Et Al: Glucagon-producing Cell Differentiationcontrasting

confidence: 45%

Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells

Suzuki¹,

Murakami²,

Samejima³

et al. 2009

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…Antizyme-1 was found in the nucleus co-localized with ODC after treatment of carcinoma cells with polyamines or polyamine analogs (41). It was suggested on the basis of these experiments, which utilized an ODC fused to green fluorescent protein, that antizyme may be involved in nucleocytoplasmic shuttling of ODC (41). Antizyme and ODC accumulated in the nucleus after treatment with a proteasome inhibitor (40), which would also be consistent with a nuclear degradation of ODC.…”

Section: Multiple Forms Of Antizymementioning

confidence: 75%

“…Translocation of antizyme-1 to the nucleus occurs during mouse development (40). Antizyme-1 was found in the nucleus co-localized with ODC after treatment of carcinoma cells with polyamines or polyamine analogs (41). It was suggested on the basis of these experiments, which utilized an ODC fused to green fluorescent protein, that antizyme may be involved in nucleocytoplasmic shuttling of ODC (41).…”

Section: Multiple Forms Of Antizymementioning

confidence: 99%

Regulation of Ornithine Decarboxylase

Pegg

2006

Journal of Biological Chemistry

408

416

View full text Add to dashboard Cite

Ornithine decarboxylase (ODC) initiates the polyamine biosynthetic pathway. The amount of ODC is altered in response to many growth factors, oncogenes, and tumor promoters and to changes in polyamine levels. Susceptibility to tumor development is increased in transgenic mice expressing high levels of ODC and is decreased in mice with reduced ODC due to loss of one ODC allele or elevated expression of antizyme, a protein that stimulates ODC degradation. This review describes key factors that contribute to the regulation of ODC levels, which can occur at the levels of transcription, translation, and protein turnover. L-Ornithine decarboxylase (ODC)2 catalyzes the first step in the polyamine biosynthetic pathway forming putrescine, which is then converted into the polyamines spermidine and spermine (1-4) (Fig. 1). In some microorganisms and in plants, putrescine can also be made from arginine via an arginine decarboxylase and subsequent conversion of the agmatine to putrescine. However, evidence for a mammalian arginine decarboxylase is controversial (5), and ODC provides the only established route for polyamine synthesis de novo. Polyamine content plays important roles in both normal and neoplastic growth and alterations of polyamine synthesis via changes in ODC content occur in response to tumor promoters and carcinogens (2, 3).ODC is very highly regulated, and ODC activity varies in response to many stimuli. These alterations in activity are brought about by changes in the amount of ODC protein, which turns over very rapidly. ODC degradation is controlled by a protein termed antizyme, which responds to polyamine concentration. ODC is also regulated at the level of transcription and the ODC gene is one of the targets of the Myc/Max transcription factor. A third level of regulation occurs in the translation of ODC mRNA. This brief review discusses these aspects of ODC and some relevant structural and comparative data focusing on relatively recent studies. Summaries of the vast literature describing earlier work on ODC, the myriad of factors altering its activity, and its value as a drug target are contained in previous reviews (2-4, 6). ODC Structure and ActivityODC is a pyridoxal phosphate (PLP)-dependent amino acid decarboxylase. Biochemical studies showed that it is a homodimer with two active sites each made up of residues from both subunits (7). Crystallographic determination of the structures of mammalian and Trypanosoma brucei ODCs (8, 9) confirmed these observations. The structure of eukaryote ODC is that of a group IV decarboxylase, structurally homologous to the bacterial and plant arginine decarboxylases, bacterial diaminopimelic acid decarboxylase, and alanine racemase but unrelated to the bacterial ODCs.Eukaryotic ODCs are, in general, highly specific for L-ornithine with a very weak activity on L-lysine and an even lower activity on L-arginine (10). However, a homolog was isolated from Paramecium bursaria chlorella virus. This protein has a key amino acid substitution (Glu for Asp) in a residue that ...

show abstract

“…To our knowledge, this is the first report which has investigated the use of atypical subcellular targeting for this purpose. The native compartment for ODC is the cytosol, although some ODC also accumulates in the nucleus [34][35][36][37][38][39]. ODC enzyme activity has also been detected in isolated mitochondria and chloroplasts [40].…”

Section: Discussionmentioning

confidence: 99%

Modulation of Polyamine Biosynthesis in Transformed Tobacco Plants by Targeting Ornithine Decarboxylase to an Atypical Subcellular Compartment

Nölke¹,

Schneider²,

Agdour³

et al. 2008

TOBIOTJ

View full text Add to dashboard Cite

Ornithine decarboxylase (ODC) is a cytosolic enzyme that catalyses the direct decarboxylation of L-ornithine to putrescine, one of the rate-limiting steps of polyamine biosynthesis in plants. We targeted recombinant human ODC to the cytosol and apoplast of transformed tobacco (Nicotiana tabacum) plants, and evaluated the impact of subcellular compartmentalization on the accumulation of the enzyme and its corresponding metabolic product. Immunoblot analysis showed that human ODC accumulated to high levels in both the cytosol and apoplast of transiently transformed tobacco leaves. In stably transformed tobacco plants with ODC targeted to the apoplast, enzyme activity increased by up to 32-fold (P < 0.001) and putrescine levels increased by up to 8.5-fold (P < 0.05) compared to wild type plants. These results demonstrate that the subcellular targeting of polyamine pathway enzymes may provide a useful strategy to enhance the accumulation and activity of enzymes involved in polyamine biosynthesis and may increase metabolic flux toward desired end products.

show abstract

Intracellular Localization of Ornithine Decarboxylase and Its Regulatory Protein, Antizyme-1

Cited by 34 publications

References 20 publications

Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells

Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells

Regulation of Ornithine Decarboxylase

Modulation of Polyamine Biosynthesis in Transformed Tobacco Plants by Targeting Ornithine Decarboxylase to an Atypical Subcellular Compartment

Contact Info

Product

Resources

About