A fully active catalytic domain of bovine aspartyl (asparaginyl) beta-hydroxylase expressed in Escherichia coli: characterization and evidence for the identification of an active-site region in vertebrate alpha-ketoglutarate-dependent dioxygenases.

Jia, Steve; McGinnis, Kathleen A.; VanDusen, William J.; Burke, Catherine; Kuo, Amy G.; Griffin, Patrick R.; Sardana, Mohinder K.; Elliston, Keith O.; Stern, Andrew M.; Friedman, Paul A.

doi:10.1073/pnas.91.15.7227

Cited by 54 publications

(54 citation statements)

References 33 publications

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“…The molecular mechanisms by which AAH regulates cell motility are uncertain; however, evidence suggests that AAH may mediate its effects on cell migration by activating notch signaling pathways. In this regard, functional studies have demonstrated that AAH catalyzes post-translational hydroxylation of ß-carbons of aspartyl and asparaginyl residues present in EGFlike domains of certain proteins (8,28,29). The consensus sequence for AAH hydroxylation is present in the EGF-like domains of notch, notch homologs and the ligand jagged (8).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of humbug promotes malignant progression in human gastric cancer cells

Lee

2008

Oncol Rep

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Abstract. Two human gastric cancer cell lines of differing invasive potential, SNU-484 and SNU-638 cells, were examined using subtractive suppression hybridization in a search for any genes associated with metastasis. Of the eight cDNAs identified as being differentially expressed genes, it was determined that humbug, which encodes a truncated isoform of aspartyl (asparaginyl) ß-hydroxylase (AAH) missing catalytic domain, was overexpressed in highly invasive SNU-638 cells. Expression analysis showed that the mRNA expression level of humbug was correlated with invasive potential in various human gastric cancer cell lines. The forced expression of humbug to the human gastric cancer cell line AGS increased its anchorage-independent growth in 0.3% agar without affecting cell proliferation. Furthermore, humbug-transfected cells migrated more actively and showed an increased invasion rate relative to vector-transfectants or parental AGS in vitro. This is the first demonstration that humbug, a truncated form of AAH, can be overexpressed during the malignant progression of human gastric cancer cells and that it can function as a metastasis-inducing gene.

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Section: Discussionmentioning

confidence: 99%

Overexpression of humbug promotes malignant progression in human gastric cancer cells

Lee

2008

Oncol Rep

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“…It specifically hydroxylates the Asp or Asn residue in certain epidermal growth factor-like domains of several proteins, including Notch and its homologues, Gas6/Axl, laminin, mucin, and other extracellular matrix molecules. 14,[29][30][31][32][33][34] Knockout of AAH in mice leads to developmental defects and an increased incidence of intestinal neoplasia, 35 and knockdown of AAH inhibits the migration of NIH-3T3 cells 15 and cholangiocarcinoma cells. 14 Overexpression of AAH was found in colon cancer, breast cancer, neuroblastoma, pancreatic cancer, and other tumors.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Aspartyl-(Asparaginyl)-β-Hydroxylase in Hepatocellular Carcinoma Is Associated With Worse Surgical Outcome

et al. 2010

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The association between the overexpression of aspartyl-(asparaginyl)-b-hydroxylase (AAH) and the invasiveness of hepatocellular carcinoma (HCC) in vitro has been reported. However, the prognostic value of AAH expression in HCC remains unclear. The purpose of this study was to investigate the relationship between AAH expression, tumor recurrence, and patient survival. We identified AAH as the most overexpressed gene in HCC by way of complementary DNA microarray hybridization. A prospective study of 233 patients undergoing curative resection indicated that AAH expression was an independent factor affecting recurrence (hazard ratio [HR] 3.161, 95% confidence interval [CI] 2.115-4.724, P < 0.001) and survival (HR 2.712, 95% CI 1.734-4.241, P < 0.001). Patients with AAH overexpression had a poorer prognosis than those with AAH underexpression (P < 0.001 for both recurrence and survival). In Barcelona Clinic Liver Cancer stage A patients with AAH overexpression or underexpression, the tumor recurrence and survival rates were also statistically different (45% and 85% versus16% and 33% in 1-and 3-year cumulative recurrence rates, respectively; 73% and 37% versus 90% and 80% in 1-and 3-year survival rates, respectively; P < 0.001 for both). Furthermore, in stage A patients with tumors measuring 5 cm in diameter, the time to recurrence was 26.7 6 1.6 versus 51.9 6 2.8 months, and the 1-and 3-year survival rates were 97% and 52% versus 100% and 90% in AAH overexpression and underexpression patients, respectively (P < 0.001 for both). Conclusion: AAH overexpression in HCC is strongly correlated with worse surgical outcome, and this molecule likely provides a more precise prognostic predictor in early stage HCCs. (HEPATOLOGY 2010;52:164-173) H epatocellular carcinoma (HCC) is one of the most prevalent malignant neoplasms worldwide 1 and is the second leading cause of cancer-related deaths in China.2 Both hepatic resection and liver transplantation are considered as potential curative treatments for well-selected HCC patients. As far as curative resection is concerned, surgical prognosis for many patients with HCC is not favorable due to the likelihood of intrahepatic and extrahepatic recurrence, which leads to a high mortality rate.3-5 Several prognostic staging systems have been established in clinical practice allowing clinicians to predict HCC outcome.6-8 Nevertheless, correlations are not always found between tumor stage and the actual prognosis, and this phenomenon is more common in patients with early HCC than in those with advanced HCC. Considering that HCC is increasingly diagnosed and resected at an early stage and that current staging systems have some limitations in the prognostic evaluation of early HCC, 4,9,10 efforts have been made to

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“…Importantly, the consensus sequence for AAH hydroxylation is also present in the epidermal growth domains of Notch and oncogenic Notch homologs; Notch has a demonstrated role in neuronal migration during development. AAH protein contains a relatively compact and highly charged carboxyl region that can be proteolytically cleaved from the amino terminal region to generate an approximately 52-kd or 56-kd catalytically active fragment (Jia et al, 1992(Jia et al, , 1994Wang et al, 1991). Site-directed mutagenesis studies demonstrated that the 675 His residue present in the C-terminal fragment is essential for catalytic activity (Dinchuk et al, 2000;Jia et al, 1992) and that the 675 His 3 Ala mutated human AAH cDNA exerts a dominant-negative phenotype with respect to AAH activity in transfected cells (Dinchuk et al, 2000;Ince et al, 2000).…”

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confidence: 99%

Role of the Aspartyl-Asparaginyl-β-Hydroxylase Gene in Neuroblastoma Cell Motility

Sepe

Lahousse

Gemelli

et al. 2002

Laboratory Investigation

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SUMMARY:Aspartyl (asparaginyl) ␤-hydroxylase (AAH) is overexpressed in various malignant neoplasms, and high levels of immunoreactivity mainly occur in infiltrating or metastasized tumors. In addition, AAH is abundantly expressed in normally invasive placental trophoblastic cells. These observations led to the hypothesis that AAH may have a role in motility and aggressive behavior of tumor cells. The present study demonstrates that AAH is overexpressed in primary human malignant neuroectodermal tumors, including medulloblastomas and neuroblastomas, and that AAH expression is at a low level or undetectable in the normal mature brain. In the Sy5y neuroblastoma cell line, endogenous expression of the~86-kd AAH protein was demonstrated by Western blot analysis, and immunoreactivity predominantly localized to the cell surface by immunocytochemical staining and FACS analysis. Sy5y cells that were stably transfected with the human AAH cDNA had increased levels of proliferating cell nuclear antigen and Bcl-2, and reduced levels of p21/Waf1 and p16. In addition, increased AAH expression enhanced Sy5y cell motility, whereas antisense oligodeoxynucleotide inhibition of AAH significantly reduced Sy5y cell motility and increased the levels of p21/Waf1 and p16. The findings suggest that AAH overexpression contributes to the malignant phenotype of neuroectodermal tumor cells by increasing motility and enhancing proliferation, survival, and cell cycle progression. Because AAH expression is at a low level or undetectable in normal brain, the AAH gene may be a target for treating primitive neuroectodermal tumors. (Lab Invest 2002, 82:881-891).

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A fully active catalytic domain of bovine aspartyl (asparaginyl) beta-hydroxylase expressed in Escherichia coli: characterization and evidence for the identification of an active-site region in vertebrate alpha-ketoglutarate-dependent dioxygenases.

Cited by 54 publications

References 33 publications

Overexpression of humbug promotes malignant progression in human gastric cancer cells

Overexpression of humbug promotes malignant progression in human gastric cancer cells

Overexpression of Aspartyl-(Asparaginyl)-β-Hydroxylase in Hepatocellular Carcinoma Is Associated With Worse Surgical Outcome

Role of the Aspartyl-Asparaginyl-β-Hydroxylase Gene in Neuroblastoma Cell Motility

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