Evidence of a Role for Antizyme and Antizyme Inhibitor as Regulators of Human Cancer

Olsen, Rachelle R.; Zetter, Bruce R.

doi:10.1158/1541-7786.mcr-11-0178

Cited by 46 publications

(50 citation statements)

References 64 publications

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“…Both AZ and AZin have been shown to function outside of the polyamine pathway (for review see Olsen and Zetter 2011). The realization that AZ might control cell growth without affecting polyamine levels followed observations that AZ could degrade proteins other than ODC.…”

Section: Discussionmentioning

confidence: 99%

Antizyme (AZ) regulates intestinal cell growth independent of polyamines

et al. 2014

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Since antizyme (AZ) is known to inhibit cell proliferation and to increase apoptosis, the question arises as to whether these effects occur independently of polyamines. Intestinal epithelial cells (IEC-6) were grown in control medium and medium containing 5mM difluoromethylornithine (DFMO) to inhibit ODC, DFMO + 5μM spermidine (SPD), DFMO+ 5μM spermine (SPM), or DFMO+ 10 μM putrescine (PUT) for 4 days and various parameters of growth were measured along with AZ levels. Cell counts were significantly decreased and mean doubling times were significantly increased by DFMO. Putrescine restored growth in the presence of DFMO. However, both SPD and SPM when added with DFMO caused a much greater inhibition of growth than did DFMO alone, and both of these polyamines caused a dramatic increase in AZ. The addition of SPD or SPM to media containing DFMO + PUT significantly inhibited growth and caused a significant increase in AZ. IEC-6 cells transfected with AZ-siRNA grew more than twice as rapidly as either control cells or those incubated with DFMO, indicating that removal of AZ increases growth in cells in which polyamine synthesis is inhibited as well as in control cells. In a separate experiment the addition of SPD increased AZ levels and inhibited growth of cells incubated with DFMO by 50%. The addition of 10 mM asparagine (ASN) prevented the increase in AZ and restored growth to control levels. These results show that cell growth in the presence or absence of ODC activity and in the presence or absence of polyamines depends only on the levels of AZ. Therefore, the effects of AZ on cell growth are independent of polyamines.

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Section: Discussionmentioning

confidence: 99%

Antizyme (AZ) regulates intestinal cell growth independent of polyamines

et al. 2014

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“…Consistent with their crucial regulatory roles, fluctuations in intracellular polyamine levels are rigorously controlled during cell growth and differentiation via fine-tuning the balance between the biosynthesis, degradation, and uptake of polyamines. Aberrant accumulation of polyamines is associated with pathological consequences, including many types of cancer (3)(4)(5).…”

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confidence: 99%

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Chen

Hsieh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polyamines are organic polycations essential for cell growth and differentiation; their aberrant accumulation is often associated with diseases, including many types of cancer. To maintain polyamine homeostasis, the catalytic activity and protein abundance of ornithine decarboxylase (ODC), the committed enzyme for polyamine biosynthesis, are reciprocally controlled by the regulatory proteins antizyme isoform 1 (Az 1 ) and antizyme inhibitor (AzIN). Az 1 suppresses polyamine production by inhibiting the assembly of the functional ODC homodimer and, most uniquely, by targeting ODC for ubiquitin-independent proteolytic destruction by the 26S proteasome. In contrast, AzIN positively regulates polyamine levels by competing with ODC for Az 1 binding. The structural basis of the Az 1 -mediated regulation of polyamine homeostasis has remained elusive. Here we report crystal structures of human Az 1 complexed with either ODC or AzIN. Structural analysis revealed that Az 1 sterically blocks ODC homodimerization. Moreover, Az 1 binding triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC, which illustrates how a substrate protein may be primed upon association with Az 1 for ubiquitin-independent proteasome recognition. Dynamic and functional analyses further indicated that the Az 1 -induced binding and degradation of ODC by proteasome can be decoupled, with the intrinsically disordered C-terminal tail fragment of ODC being required only for degradation but not binding. Finally, the AzIN-Az 1 structure suggests how AzIN may effectively compete with ODC for Az 1 to restore polyamine production. Taken together, our findings offer structural insights into the Az-mediated regulation of polyamine homeostasis and proteasomal degradation.polyamine homeostasis | ornithine decarboxylase | antizyme | antizyme inhibitor | ubiquitin-independent proteolysis P olyamines are multivalent organic cations that are ubiquitous and essential in eukaryotes (1). With their polycationic characteristics, these compounds are known to modulate the structural and functional properties of nucleic acids and proteins via electrostatic interactions, in turn affecting cell growth and differentiation by influencing the underlying cellular processes (1, 2). Consistent with their crucial regulatory roles, fluctuations in intracellular polyamine levels are rigorously controlled during cell growth and differentiation via fine-tuning the balance between the biosynthesis, degradation, and uptake of polyamines. Aberrant accumulation of polyamines is associated with pathological consequences, including many types of cancer (3-5).Regulation of polyamine homeostasis is achieved mainly by adjusting the catalytic activity and protein abundance of ornithine decarboxylase (ODC), a homodimeric and pyridoxal 5ʹ-phosphatedependent enzyme that catalyzes the committed and rate-limiting step in polyamine biosynthesis, through the actions of the regulatory proteins antizyme isoform 1 (Az 1 ) and antizyme inhibitor (AzIN) (3, 6). E...

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“…OAZ1 is an evolutionarily conserved protein that regulates cellular metabolism through its involvement in the degradation of substrates in a ubiquitin-independent manner. It also functions as the key regulator of polyamines homeostasis [11], and it is generally recognized to be a potent tumor suppressor gene, as the expression of OAZ1 can inhibit cellular growth and tumorigenesis [12]. …”

Section: Discussionmentioning

confidence: 99%

Assay of OAZ1 mRNA Levels in Chronic Myeloid Leukemia Combined with Application of Leukemia PCR Array Identified Relevant Gene Changes Affected by Antizyme

Wang

et al. 2013

Acta Haematol

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Ornithine decarboxylase antizyme (OAZ) has recently emerged as a potential therapeutic target in various malignant tumors because it plays vital roles in cellular functions including proliferation, differentiation, apoptosis and genomic stability. Therefore, there is a significant interest in discovering its function in chronic myeloid leukemia (CML). Firstly, OAZ1 mRNA was measured by qRT-PCR in 43 cases with CML and 23 controls, and we demonstrated that it is significantly down-regulated in CML patients. To further understand its functions in CML pathogenesis, OAZ1 was overexpressed, and the human leukemia PCR array analysis was used to monitor the expression of key genes commonly involved in leukemia development, classification and therapeutic response. We found several favorable up-regulation factors including CXCL10, DAPK1 and IKZF3. In conclusion, OAZ1 may be a useful therapeutic target in CML due to its potential ability to induce erythroid differentiation and cell apoptosis. These functions were proven to be associated with several gene changes that were directly or indirectly caused by OAZ1. The mechanism of how OAZ1 affects other genes remains to be elucidated.

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Evidence of a Role for Antizyme and Antizyme Inhibitor as Regulators of Human Cancer

Cited by 46 publications

References 64 publications

Antizyme (AZ) regulates intestinal cell growth independent of polyamines

Antizyme (AZ) regulates intestinal cell growth independent of polyamines

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Assay of OAZ1 mRNA Levels in Chronic Myeloid Leukemia Combined with Application of Leukemia PCR Array Identified Relevant Gene Changes Affected by Antizyme

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