Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review ANG (angiogenin, ribonuclease, RNase A family, 5) Shouji Shimoyama Gastrointestinal Unit, Settlement Clinic, 4-20-7, Towa, Adachi-ku, Tokyo, 120-0003, Japan (SS) Published in Atlas Database: June 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/ANGID635ch14q11.html DOI: 10.4267/2042/44976 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology belongs to the RNAse superfamily, being 35% identical and 68% homologous to the pancreatic RNAse A sequence. The overall crystal structure of ANG shows a similarity to, but the biological actions of ANG differ distinctly from those of RNAse A. ANG possesses two distinct regions: a ribonucleolytic and a noncatalytic site, both being critical for angiogenic activity. Besides the ribonucleolytic activity, ANG differs from RNAse A in noncatalytic activities such as interactions with endothelial and smooth muscle cells and subsequent cellular responses in the events of neovascularization, including basement membrane degradation, signal transduction, and nuclear translocation. Identity Other names: ALS9; HEL168; MGC71966; RNASE4; RNASE5 HGNC (Hugo): ANG Location: 14q11.2 MGC22466; DNA/RNA Expression ANG mRNA is expressed in a wide spectrum of cells including neoplastic cells as well as normal epithelial cells, fibroblasts, peripheral blood cells, and vascular endothelial cells. Localisation Starts at 2152336 and ends at 2162345 in NCBI reference sequence NT_026437.12. Gene map locus is available at NCBI Nucleotide. Total length of ANG DNA is 10010 nucleotides. The coding region starts at 2162723 and ends at 2162166 including stop codon TAA. Strikingly, ANG localizes freely in the circulation, and is translocated into the nucleus. Nuclear translocation of ANG triggers subsequent cell proliferation. However, the precise mechanisms for why serum ANG is inactive and continuous angiogenesis does not take place remain unknown. Protein Description Function The amino acid sequence is available at NCBI protein locus AAA51678. It consists of a signal peptide from amino acid 1 to 24 and a mature peptide from amino acid 25 to 147. ANG is a basic, single chain potent blood-vessel inducing protein with a molecular weight of 14 kDa which was originally discovered in conditioned media of a human colon carcinoma cell line HT-29. ANG Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) I. Ribonuclease activity The catalytic activity of ANG is several orders of magnitude weaker than that of RNAse A, this being partly due to the partial occupation of the pyrimidinebinding pocket of RNAse A by glutamine-117 residue so that the substrate binding is compromised. Key amino acids for the ribo- 244 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S The secondary structure elements of human ANG are depicted by purple boxes. The numbers on the upper and lower sides of each element indicate respectively the beginning and end amino acid residue positions (Acharya et al., 1994). The whole amino acid sequences are shown below and the signal peptide sequences (1-24) are enclosed by box. The H elements form helix structure (Acharya et al., 1994). Key amino acids for the ribonucleolytic activity of ANG (His13, Lys40, and His114) are indicated by plus (+) signs, and residues necessary for angiogenesis (60-68 and 109) are underlined. suggesting that the ANG-fibulin-1 complex modulates new blood vessel formation and stabilization. 2) Signal transduction Besides the 42 kDa ANG receptor, a 170 kDa molecule later found on the endothelial surface is responsible for signal transduction, an important process leading to cell proliferation. ANG activates several secondary message cascades such as extracellular signal related kinase 1/2 (ERK1 and ERK2), protein kinase B/Akt, and stress-associated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). 3) Nuclear translocation The nuclear mechanisms underlying the function of ANG remain elusive. Internalization could involve cell surface ANG binding to proteins as well as to other molecules such as proteoglycans, followed by endocytosis. In this event, ANG interacts directly with intracellular protein alpha-actinin-2 followed by translocation into the nucleus through the nuclear pore in a passive manner. After nuclear retention, ANG binds to carrier proteins through a sequence 29IMRRRGL-35 (nuclear localization signal) of ANG and to the ANG-binding element of ribosomal DNA (CTCT repeats) and subsequently, stimulates ribosomal RNA transcription. Nuclear translocation is essential for cell proliferation since it is considered a third messenger and promotes gene activation and transcription events, and inhibition of the nuclear translocation of angiogenin abolishes ANG-induced angiogenesis. Interestingly, the expression of cell surface receptors responsible for internalization as well as for the nuclear translocation of ANG also depends on the cell density. nucleolytic activity of ANG are His13, Lys40, or His114 of ANG, a catalytic triad, but mutations of these amino acids also reduce ANG induced angiogenesis, suggesting that the ribonucleolytic activity of ANG, although weak, is necessary for the angiogenic activity of ANG. Furthermore, several arginines are essential for ribonucleolytic and angiogenic activities. II. Angiogenic activity In addition to the catalytic activity, cell binding sites which encompass residues 60-68 of the surface loop as well as asparagine-109 are necessary for angiogenesis. The variants undergoing alterations of these residues lack any angiogenic activity while the enzymatic activity remains intact. Inversely, replacing the surface loop in RNAse A (residues 59-73) with the corresponding region of ANG (residue 57-70) bestows a neovascularization activity to the RNAse A. 1) Basement membrane degradation Amino acid residues from Lys60 to Asn68 of the ANG constitute a cell surface receptor binding site. Accordingly, a 42 kDa endothelial cell surface protein was identified as an ANG binding protein, which was later found to be a smooth muscle type alpha-actin. The ANG-actin complex dissociates from the cell surface and activates a tissue type plasminogen activator, thus accelerating degradation of the basement membrane and extracellular matrix that allows endothelial cells to penetrate or migrate through the extracellular matrix more easily, an initial step of neovascularization. Furthermore, fibulin-1, an important molecule for stabilization of the blood vessel wall, binds to ANG, Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 245 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S III. Roles of ANG in physiological angiogenesis The above biological events, which are distinct from those of RNAse A, are regulated tightly by the cell density-dependent expression of ANG receptors. The discovery of the uniquely regulated expression of ANG receptors provides us with the following conceivable mechanisms for ANG related angiogenesis. In the region where neovascularization is required, ANG binds to the endothelial surface 42 kDa receptor, and the ANG-42 kDa receptor complex dissociates from the cell surface and stimulates proteolytic activity, thus facilitating the penetration of endothelial cells through the extracellular matrix. After the leading cells migrate away, the endothelial cell density in the vicinity of migrating cells might be sparse, and such cell sparsity triggers the endothelial proliferation machinery that includes signal transduction, ANG internalization, and nuclear translocation. A 170 kDa receptor is one of the receptors responsible for this orchestrated process. Once the microenvironment is filled up with the sufficient amount of endothelial cells and the vascular network is established, such cell proliferating events diminish. Therefore, the above cell density dependent biological events are intelligent mechanisms where the proliferation machinery and subsequent angiogenic switch are on when neovascularization is needed while they are off to prevent unwanted angiogenesis. establishment or metastasis of human tumors in athymic mice. These compounds include a monoclonal antibody, antisense oligonucleotides complementary to the AUG translational start site region of ANG, translocation blocker, enzymatic inhibitor targeting ANG enzymatic active site, ANG binding polypeptide complementary to the receptor binding site of ANG, and internalization pathway blocker. Female breast cancer Disease Female breast cancer is globally the most common cancer with an annual incidence of 1,15 million worldwide. It is also the leading cause of death, with a mortality rate of 133 per million. Breast cancer incidence rates have increased in most geographic regions. Prognosis The ANG level in sera and the roles of ANG in breast cancer patients seem to be conflicting. Some studies found significantly increased serum ANG in breast cancer patients in comparison with normal controls while other studies failed to find such a difference. The serum ANG level is significantly decreased after breast cancer resection, suggesting that the source of ANG is at least in part the breast cancer cells. However, there is conflicting evidence concerning the role of ANG. The correlation between ANG expression in tissue or in sera and patient survival was inverse, neutral, or even positive. The absence of any increase in serum ANG levels in early stage breast cancer patients suggests that ANG may have clinical implications when breast cancer progresses to the advanced stage. Homology Of the 123 amino acids of human ANG, 43 (35%) and 25 are respectively identical to human pancreatic RNAse or to other RNAse, and 16 are conservative replacements, constituting an overall homology of 68%. Pancreas cancer Implicated in Disease The pancreas is composed of exocrine (acinar glands and pancreas duct) and endocrine (islets of Langerhans) components. Both can give rise to malignant neoplasms, but adenocarcinoma arising from the pancreatic ducts is representative of all pancreatic cancers. Prognosis Pancreatic cancer is one of the most aggressive diseases with most cancers already in later stages at presentation, the 5-year survival rate being around 5% both in USA and in Europe. Investigations concerning ANG expression in pancreatic cancer are scarce. ANG in sera is elevated in pancreatic cancer patients as compared with healthy volunteers, and increased ANG mRNA in tissue or increased ANG in sera has been correlated with cancer aggressiveness. In addition, the involvement of ANG in the cancer microenvironment has been suggested by findings of the ANG expression in chronic pancreatitis adjacent to pancreatic cancer but not in pure chronic pancreatitis. Cancer derived fibroblasts also express ANG. Various cancers Note There is growing evidence that increased ANG expression in tissue and/or in sera is correlated with tumor aggressiveness. These facts are explained at least in part by the hypothesis that ANG in malignancy plays roles in the proliferation and migration of malignant cells, mimicking endothelial cell behavior during physiological angiogenesis. As described earlier, ANG could activate proteolytic activity, so that ANGexpressing malignant cells are allowed to invade through the extracellular matrix and enter into the bloodstream. In addition, the continuous translocation of ANG to the nucleus of HeLa cells in a cell densityindependent manner suggests that cancer cells are also targets for ANG, and that ANG per se is a contributing factor for sustained cell growth and the constant supply of ribosomes, a characteristic of malignant cells. Several ANG antagonists have been introduced and some have proved to be effective inhibitors for the Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 246 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S the disease is a strong predictor of survival, suggesting that early detection is needed for improvement in treatment outcomes. Prognosis Immunoreactivity in lung cancer tissue is correlated with tumor size and positive nodal involvement. Recently, the detection of ANG in exhaled breath condensate has been achieved, and breath based ANG may help in the early detection of lung cancer. Cytogenetics DNA damage in 14q11.2 was found in asbestosexposed lung cancer patients. Gastric cancer Disease Gastric cancer, the third most common cancer and the second leading cause of cancer death among men, arises in an estimated one million new cases in both sexes worldwide. Gastric cancer is anatomically classified as noncardia and cardia cancers, and the former incidence has declined while the latter incidence has increased. Helicobacter pylori infection is one of the risk factors for noncardia cancer. Adenocarcinomas account for a large majority of gastric cancer histologic diagnoses. Prognosis The 5-year survival rate of gastric cancer in Japan is double that of the United States and Europe. The better treatment outcomes are ascribed partly to the social screening program that attempts to capitalize on the benefit of early detection, and partly to systematic lymph node dissection. ANG in sera is increased in gastric cancer patients and is decreased by resection, suggesting gastric cancer to be a source of ANG. Increased mRNA expression in gastric cancer tissues or increased serum ANG levels is correlated with cancer progression, proliferation ability, and poor patient prognosis. Liver cancer Disease The global incidence and mortality rate of liver cancer is ranked among top 5 (in men) and top 10 (in women) cancer types. The hepatitis B virus and hepatitis C virus are the most important risk factors for liver cancer. Histologic classification separates hepatocellular carcinoma (HCC) (liver cell origin) from cholangiocarcinoma, which arises from intrahepatic bile ducts. HCC is the most common histology of liver cancer which is characterized by vigorous neovascularization. Prognosis The serum ANG is increased in hypervascular hepatocellular carcinoma. The serum ANG level decreases after therapy but again increases at recurrence, suggesting the usefulness of serum ANG measurement for monitoring the disease and prediction of patient survival. However, other investigators found a neutral correlation between serum ANG and survival. The ANG immunoreactivity is correlated with poorer histological differentiation. Cytogenetics 14q11.2 is found to be highly amplified in hepatoblastoma. Colorectal cancer Disease Colon cancer is the fourth most commonly diagnosed cancer and fourth most frequent cause of cancer death among men. Colon cancer incidence rates have increased in most parts of the world. Typically, there is a pathologic evolution from benign adenomas to cancer (adenoma-carcinoma sequence), so that colorectal cancer screening aims to detect lesions at the adenoma stage and interrupt the adenoma carcinoma sequence, ultimately reducing colorectal cancer incidence and mortality. Prognosis Colorectal cancer exhibits increased serum ANG concentration, and the degree of elevation is correlated with cancer progression. ANG message expression in colorectal cancer tissue has also been correlated with poor patient survival. Cytogenetics Overexpression of the 14q11.1-14q11.2 product was observed in a colon adenocarcinoma cell line. Prostate cancer Disease Prostate cancer is the second most frequently diagnosed cancer among men. Prognosis is excellent for early stage disease while it is poor for those diagnosed with advanced cases, pointing to the benefit of earlier diagnosis. Measurement of prostate specific antigen helps to detect biologically indolent prostate cancer. Prognosis The immunoreactivity of ANG is more evident according to prostate epithelial cells evolution from a benign to an invasive phenotype. In vitro analyses using prostate cancer cell line have elucidated that ANG is one of the elements responsible for tumorigenicity and tumor growth. Furthermore, serum ANG is more increased in hormone-refractory patients than in healthy controls. Lung cancer Disease Lung cancer is the most frequently diagnosed cancer among men. The mortality rate is the highest among men and the second highest among women worldwide. Cigarette smoking is the most important risk factor for lung cancer. The main histologic types of lung cancer are adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma. The stage of Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 247 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S overwhelmingly the most common. The majority of cancers of the kidney are renal cell carcinomas, which arise from renal tubules. On the other hand, cancer of the renal pelvis designated as transitional cell carcinoma comprises the minority. Prognosis The serum level of ANG is increased in renal cell carcinoma and bladder cancer; however, the increase in serum ANG level does not correlate with patient survival for renal cell carcinoma. On the other hand, increased serum ANG or ANG message in urothelial cancer correlates with poor patient survival or cancer progression. Recently, ANG in the urine has been found to be increased in bladder cancer patients. Leukemia Disease Leukemias are malignancies that affect blood-forming stem cells in the bone marrow. Leukemia, a heterogeneous group of malignancies, is classified into several subtypes according to the major cell type such as acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), etc. Acute types refer to cancers arising in immature stem cells while chronic types refer to cancers arising in mature stem cells. Prognosis The ANG level in sera was increased in AML and CML, although other investigators failed to find such correlation. In sharp contrast to the clinical significance of serum ANG in other solid tumors, elevated serum ANG in AML and CML is correlated with better patient survival. Cytogenetics 14q11.2 is one of the risk foci for ALL. Melanoma Disease Melanoma is placed as the leading cause of skin cancer death and its incidence has dramatically increased over the last ten years. It is characterized as having a notorious resistance to currently available therapies so that early detection and intervention is needed. Prognosis Survival clearly worsens with increasing tumor thickness. Thin lesions exhibit excellent survival outcomes while the MST of patients with advance cases is around 8 months. The ANG in sera is increased in melanoma patients, and increased serum ANG correlates with malignancy potential, accordingly, ANG contributes directly to A375 melanoma cell proliferation. However, other investigators failed to find such a correlation. Hodgkin and non-hodgkin lymphomas Disease Lymphomas, malignancies of the lymphoid cells, are divided on the basis of their pathologic features into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). HL almost always develops in a lymph node or other lymphoid structure and spread to nearby nodes. HL is characterized by the presence of Hodgkin Reed Sternberg cells. It is one of the most common cancers diagnosed in younger persons. The proportions of patients being diagnosed below 50 years old accounts for 60%. NHL occurs in more elderly patients in the context of HIV-related immunosuppression. NHL with HIV shows extensively poorer survivals than those without HIV. Prognosis In sharp contrast to the other solid malignancies, serum ANG concentrations in patients with HL or NHL are less than or the same as those in healthy controls. Increased serum ANG renders no or an inverse impact on survival in NHL patients. Cytogenetics One subtype of NHL experiences multiple translocations at 14q11.2. Gynecological cancers Disease Cancers of the uterus and ovary are respectively the second and the sixth most frequently diagnosed cancer among women. Cancer of the uterus is further classified as cancer of the cervix and corpus, and cancer of the cervix uteri shows the highest incidence among the three gynecological malignancies. Cancer of the cervix uteri can be attributed to persistent infection with carcinogenic genotypes of human papilloma virus. The three most common histological types of cancer of the cervix uteri are squamous, adenosquamous, and adenocarcinoma. Adenocarcinoma is the most common histology of cancer of the corpus uteri and ovary. Women with ovarian cancer have poorer survival rates than those with other gynecological cancers. Prognosis Serum ANG is significantly increased in ovarian cancer patients, while other studies failed to find such a difference. Increased serum ANG concentration is correlated with cancer progression in ovary and cervix uteri. Cytogenetics Gains on 14q11.2 are associated with chemoresistant ovarian cancer. Kidney and bladder cancer Disease Kidney and bladder cancers are placed among the top ten cancer types in both sexes. Cancer of the urinary bladder most commonly originates in the urothelium, the epithelium that lines the bladder. Bladder cancer incidence is significantly higher in males than in females. There are three major histologic types of bladder cancer: transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma, the former being Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 248 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S Moroianu J, Riordan JF. Nuclear translocation of angiogenin in proliferating endothelial cells is essential to its angiogenic activity. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1677-81 References Kurachi K, Davie EW, Strydom DJ, Riordan JF, Vallee BL. Sequence of the cDNA and gene for angiogenin, a human angiogenesis factor. Biochemistry. 1985 Sep 24;24(20):5494-9 Moroianu J, Riordan JF. Identification of the nucleolar targeting signal of human angiogenin. Biochem Biophys Res Commun. 1994 Sep 30;203(3):1765-72 Strydom DJ, Fett JW, Lobb RR, Alderman EM, Bethune JL, Riordan JF, Vallee BL. Amino acid sequence of human tumor derived angiogenin. Biochemistry. 1985 Sep 24;24(20):548694 Olson KA, French TC, Vallee BL, Fett JW. A monoclonal antibody to human angiogenin suppresses tumor growth in athymic mice. Cancer Res. 1994 Sep 1;54(17):4576-9 Rybak SM, Fett JW, Yao QZ, Vallee BL. Angiogenin mRNA in human tumor and normal cells. Biochem Biophys Res Commun. 1987 Aug 14;146(3):1240-8 Russo N, Shapiro R, Acharya KR, Riordan JF, Vallee BL. Role of glutamine-117 in the ribonucleolytic activity of human angiogenin. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2920-4 Shapiro R, Strydom DJ, Olson KA, Vallee BL. Isolation of angiogenin from normal human plasma. Biochemistry. 1987 Aug 11;26(16):5141-6 Raines RT, Toscano MP, Nierengarten DM, Ha JH, Auerbach R. Replacing a surface loop endows ribonuclease A with angiogenic activity. J Biol Chem. 1995 Jul 21;270(29):17180-4 Riordan JF, Vallee BL. Human angiogenin, an organogenic protein. Br J Cancer. 1988 Jun;57(6):587-90 Chopra V, Dinh TV, Hannigan EV. Angiogenin, interleukins, and growth-factor levels in serum of patients with ovarian cancer: correlation with angiogenesis. Cancer J Sci Am. 1996 Sep-Oct;2(5):279-85 Shapiro R, Fox EA, Riordan JF. Role of lysines in human angiogenin: chemical modification and site-directed mutagenesis. Biochemistry. 1989 Feb 21;28(4):1726-32 Shimoyama S, Gansauge F, Gansauge S, Negri G, Oohara T, Beger HG. Increased angiogenin expression in pancreatic cancer is related to cancer aggressiveness. Cancer Res. 1996 Jun 15;56(12):2703-6 Shapiro R, Vallee BL. Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis. Biochemistry. 1989 Sep 5;28(18):7401-8 Barton DP, Cai A, Wendt K, Young M, Gamero A, De Cesare S. Angiogenic protein expression in advanced epithelial ovarian cancer. Clin Cancer Res. 1997 Sep;3(9):1579-86 Weremowicz S, Fox EA, Morton CC, Vallee BL. Localization of the human angiogenin gene to chromosome band 14q11, proximal to the T cell receptor alpha/delta locus. Am J Hum Genet. 1990 Dec;47(6):973-81 Chopra V, Dinh TV, Hannigan EV. Serum levels of interleukins, growth factors and angiogenin in patients with endometrial cancer. J Cancer Res Clin Oncol. 1997;123(3):167-72 Hallahan TW, Shapiro R, Vallee BL. Dual site model for the organogenic activity of angiogenin. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2222-6 Gho YS, Chae CB. Anti-angiogenin activity of the peptides complementary to the receptor-binding site of angiogenin. J Biol Chem. 1997 Sep 26;272(39):24294-9 Hu GF, Chang SI, Riordan JF, Vallee BL. An angiogeninbinding protein from endothelial cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2227-31 Hu GF, Riordan JF, Vallee BL. A putative angiogenin receptor in angiogenin-responsive human endothelial cells. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2204-9 Hallahan TW, Shapiro R, Strydom DJ, Vallee BL. Importance of asparagine-61 and asparagine-109 to the angiogenic activity of human angiogenin. Biochemistry. 1992 Sep 1;31(34):8022-9 Chopra V, Dinh TV, Hannigan EV. Circulating serum levels of cytokines and angiogenic factors in patients with cervical cancer. Cancer Invest. 1998;16(3):152-9 Shapiro R, Vallee BL. Identification of functional arginines in human angiogenin by site-directed mutagenesis. Biochemistry. 1992 Dec 15;31(49):12477-85 Eppenberger U, Kueng W, Schlaeppi JM, Roesel JL, et al. Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol. 1998 Sep;16(9):3129-36 Hu GF, Riordan JF. Angiogenin enhances actin acceleration of plasminogen activation. Biochem Biophys Res Commun. 1993 Dec 15;197(2):682-7 Hu GF. Neomycin inhibits angiogenin-induced angiogenesis. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9791-5 Hu GF, Strydom DJ, Fett JW, Riordan JF, Vallee BL. Actin is a binding protein for angiogenin. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1217-21 Montero S, Guzmán C, Cortés-Funes H, Colomer R. Angiogenin expression and prognosis in primary breast carcinoma. Clin Cancer Res. 1998 Sep;4(9):2161-8 Acharya KR, Shapiro R, Allen SC, Riordan JF, Vallee BL. Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2915-9 Bertolini F, Paolucci M, Peccatori F, Cinieri S, Agazzi A, Ferrucci PF, Cocorocchio E, Goldhirsch A, Martinelli G. Angiogenic growth factors and endostatin in non-Hodgkin's lymphoma. Br J Haematol. 1999 Aug;106(2):504-9 Hu G, Riordan JF, Vallee BL. Angiogenin promotes invasiveness of cultured endothelial cells by stimulation of cellassociated proteolytic activities. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12096-100 Hatzi E, Badet J. Expression of receptors for human angiogenin in vascular smooth muscle cells. Eur J Biochem. 1999 Mar;260(3):825-32 Laduron PM. From receptor internalization to nuclear translocation. New targets for long-term pharmacology. Biochem Pharmacol. 1994 Jan 13;47(1):3-13 Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S. Increased angiogenin expression in the tumor tissue and serum of urothelial carcinoma patients is related to disease progression and recurrence. Cancer. 1999 Jul 15;86(2):316-24 Moenner M, Gusse M, Hatzi E, Badet J. The widespread expression of angiogenin in different human cells suggests a biological function not only related to angiogenesis. Eur J Biochem. 1994 Dec 1;226(2):483-90 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) Shimoyama S, Gansauge F, Gansauge S, Oohara T, Kaminishi M, Beger HG. Increased angiogenin expression in 249 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S obstructive chronic pancreatitis surrounding pancreatic cancer but not in pure chronic pancreatitis. Pancreas. 1999 Apr;18(3):225-30 Bevona C, Sober AJ. Melanoma incidence trends. Dermatol Clin. 2002 Oct;20(4):589-95, vii Shimoyama S, Yamasaki K, Kawahara M, Kaminishi M. Increased serum angiogenin concentration in colorectal cancer is correlated with cancer progression. Clin Cancer Res. 1999 May;5(5):1125-30 Brunner B, Gunsilius E, Schumacher P, Zwierzina H, Gastl G, Stauder R. Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia. J Hematother Stem Cell Res. 2002 Feb;11(1):119-25 Wechsel HW, Bichler KH, Feil G, Loeser W, Lahme S, Petri E. Renal cell carcinoma: relevance of angiogenetic factors. Anticancer Res. 1999 Mar-Apr;19(2C):1537-40 Gho YS, Yoon WH, Chae CB. Antiplasmin activity of a peptide that binds to the receptor-binding site of angiogenin. J Biol Chem. 2002 Mar 22;277(12):9690-4 Etoh T, Shibuta K, Barnard GF, Kitano S, Mori M. Angiogenin expression in human colorectal cancer: the role of focal macrophage infiltration. Clin Cancer Res. 2000 Sep;6(9):354551 Glenjen N, Mosevoll KA, Bruserud Ø. Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia. Int J Cancer. 2002 Sep 1;101(1):86-94 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70 Kao RY, Jenkins JL, Olson KA, Key ME, Fett JW, Shapiro R. A small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activity. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10066-71 Hatzi E, Bassaglia Y, Badet J. Internalization and processing of human angiogenin by cultured aortic smooth muscle cells. Biochem Biophys Res Commun. 2000 Jan 27;267(3):719-25 Leland PA, Staniszewski KE, Park C, Kelemen BR, Raines RT. The ribonucleolytic activity of angiogenin. Biochemistry. 2002 Jan 29;41(4):1343-50 Hu G, Xu C, Riordan JF. Human angiogenin is rapidly translocated to the nucleus of human umbilical vein endothelial cells and binds to DNA. J Cell Biochem. 2000 Jan;76(3):45262 Ni X, Ma Y, Cheng H, Jiang M, Guo L, Ji C, Gu S, Cao Y, Xie Y, Mao Y. Molecular cloning and characterization of a novel human Rab ( Rab2B) gene. J Hum Genet. 2002;47(10):548-51 Sheen-Chen SM, Eng HL, Chen WJ, Chou FF, Chen HS. Serum level of angiogenin in breast cancer. Anticancer Res. 2000 Nov-Dec;20(6C):4769-71 Olson KA, Byers HR, Key ME, Fett JW. Inhibition of prostate carcinoma establishment and metastatic growth in mice by an antiangiogenin monoclonal antibody. Int J Cancer. 2002 Apr 20;98(6):923-9 Shimoyama S, Kaminishi M. Increased angiogenin expression in gastric cancer correlated with cancer progression. J Cancer Res Clin Oncol. 2000 Aug;126(8):468-74 Xu ZP, Tsuji T, Riordan JF, Hu GF. The nuclear function of angiogenin in endothelial cells is related to rRNA production. Biochem Biophys Res Commun. 2002 Jun 7;294(2):287-92 Bodner-Adler B, Hefler L, Bodner K, Leodolter S, et al. Serum levels of angiogenin (ANG) in invasive cervical cancer and in cervical intraepithelial neoplasia (CIN). Anticancer Res. 2001 Jan-Feb;21(1B):809-12 Liu S, Yu D, Xu ZP, Riordan JF, Hu GF. Angiogenin activates Erk1/2 in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2001 Sep 14;287(1):305-10 Chao Y, Li CP, Chau GY, Chen CP, King KL, Lui WY, Yen SH, Chang FY, Chan WK, Lee SD. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol. 2003 May;10(4):355-62 Lixin R, Efthymiadis A, Henderson B, Jans DA. Novel properties of the nucleolar targeting signal of human angiogenin. Biochem Biophys Res Commun. 2001 Jun 1;284(1):185-93 Hisai H, Kato J, Kobune M, Murakami T, Miyanishi K, et al. Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. Clin Cancer Res. 2003 Oct 15;9(13):4852-9 Olson KA, Byers HR, Key ME, Fett JW. Prevention of human prostate tumor metastasis in athymic mice by antisense targeting of human angiogenin. Clin Cancer Res. 2001 Nov;7(11):3598-605 Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, et al. Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7841-6 Pilch H, Schlenger K, Steiner E, Brockerhoff P, Knapstein P, Vaupel P. Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cells and cervical cancer-derived fibroblasts. Int J Gynecol Cancer. 2001 Mar-Apr;11(2):137-42 Shimoyama S, Kaminishi M. Angiogenin in sera as an independent prognostic factor in gastric cancer. J Cancer Res Clin Oncol. 2003 Apr;129(4):239-44 Sun W, Schuchter LM. Metastatic melanoma. Curr Treat Options Oncol. 2001 Jun;2(3):193-202 Xu ZP, Tsuji T, Riordan JF, Hu GF. Identification and characterization of an angiogenin-binding DNA sequence that stimulates luciferase reporter gene expression. Biochemistry. 2003 Jan 14;42(1):121-8 Ugurel S, Rappl G, Tilgen W, Reinhold U. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol. 2001 Jan 15;19(2):577-83 Giles FJ, Vose JM, Do KA, Johnson MM, Manshouri T, et al. Clinical relevance of circulating angiogenic factors in patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma. Leuk Res. 2004 Jun;28(6):595-604 Verstovsek S, Kantarjian H, Aguayo A, Manshouri T, et al. Significance of angiogenin plasma concentrations in patients with acute myeloid leukaemia and advanced myelodysplastic syndrome. Br J Haematol. 2001 Aug;114(2):290-5 Molica S, Vitelli G, Levato D, Giannarelli D, Vacca A, Cuneo A, Ribatti D, Digiesi G. Serum angiogenin is not elevated in patients with early B-cell chronic lymphocytic leukemia but is prognostic factor for disease progression. Eur J Haematol. 2004 Jul;73(1):36-42 Xu Z, Monti DM, Hu G. Angiogenin activates human umbilical artery smooth muscle cells. Biochem Biophys Res Commun. 2001 Jul 27;285(4):909-14 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 250 ANG (angiogenin, ribonuclease, RNase A family, 5) Shimoyama S Musolino C, Alonci A, Bellomo G, Loteta B, Quartarone E, Gangemi D, Massara E, Calabrò L. Levels of soluble angiogenin in chronic myeloid malignancies: clinical implications. Eur J Haematol. 2004 Jun;72(6):416-9 Lones MA, Heerema NA, Le Beau MM, Sposto R, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCGE08. Cancer Genet Cytogenet. 2007 Jan 1;172(1):1-11 Cho S, Beintema JJ, Zhang J. The ribonuclease A superfamily of mammals and birds: identifying new members and tracing evolutionary histories. Genomics. 2005 Feb;85(2):208-20 Vihinen P, Kallioinen M, Vuoristo MS, Ivaska J, Syrjänen KJ, Hahka-Kemppinen M, Kellokumpu-Lehtinen PL, Pyrhönen SO. Serum angiogenin levels predict treatment response in patients with stage IV melanoma. Clin Exp Metastasis. 2007;24(7):56774 Hirukawa S, Olson KA, Tsuji T, Hu GF. Neamine inhibits xenografic human tumor growth and angiogenesis in athymic mice. Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8745-52 Passam FH, Sfiridaki A, Pappa C, Kyriakou D, Petreli E, et al. Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma; relation to clinical features and response to treatment. Int J Lab Hematol. 2008 Feb;30(1):17-25 Hu H, Gao X, Sun Y, Zhou J, Yang M, Xu Z. Alpha-actinin-2, a cytoskeletal protein, binds to angiogenin. Biochem Biophys Res Commun. 2005 Apr 8;329(2):661-7 Katona TM, Neubauer BL, Iversen PW, Zhang S, Baldridge LA, Cheng L. Elevated expression of angiogenin in prostate cancer and its precursors. Clin Cancer Res. 2005 Dec 1;11(23):835863 Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, et al. Wholegenome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. Cancer Sci. 2008 Mar;99(3):564-70 Tsuji T, Sun Y, Kishimoto K, Olson KA, Liu S, Hirukawa S, Hu GF. Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation. Cancer Res. 2005 Feb 15;65(4):1352-60 Zhang H, Gao X, Weng C, Xu Z. Interaction between angiogenin and fibulin 1: evidence and implication. Acta Biochim Biophys Sin (Shanghai). 2008 May;40(5):375-80 Zhao H, Grossman HB, Delclos GL, Hwang LY, et al. Increased plasma levels of angiogenin and the risk of bladder carcinoma: from initiation ot recurrence. Cancer. 2005 Jul 1;104(1):30-5 Chan HP, Lewis C, Thomas PS. Exhaled breath analysis: novel approach for early detection of lung cancer. Lung Cancer. 2009 Feb;63(2):164-8 Duranyildiz D, Camlica H, Soydinc HO, Derin D, Yasasever V. Serum levels of angiogenic factors in early breast cancer remain close to normal. Breast. 2009 Feb;18(1):26-9 Chen Y, Zhang S, Chen YP, Lin JY. Increased expression of angiogenin in gastric carcinoma in correlation with tumor angiogenesis and proliferation. World J Gastroenterol. 2006 Aug 28;12(32):5135-9 Eissa S, Swellam M, Labib RA, El-Zayat T, El Ahmady O. A panel of angiogenic factors for early bladder cancer detection: enzyme immunoassay and Western blot. J Urol. 2009 Mar;181(3):1353-60 Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006 May 10;24(14):2137-50 Goon PK, Lip GY, Stonelake PS, Blann AD. Circulating endothelial cells and circulating progenitor cells in breast cancer: relationship to endothelial damage/dysfunction/apoptosis, clinicopathologic factors, and the Nottingham Prognostic Index. Neoplasia. 2009 Aug;11(8):771-9 Nymark P, Wikman H, Ruosaari S, Hollmén J, et al. Identification of specific gene copy number changes in asbestos-related lung cancer. Cancer Res. 2006 Jun 1;66(11):5737-43 Ibaragi S, Yoshioka N, Li S, Hu MG, Hirukawa S, Sadow PM, Hu GF. Neamine inhibits prostate cancer growth by suppressing angiogenin-mediated rRNA transcription. Clin Cancer Res. 2009 Mar 15;15(6):1981-8 Song J, Wang J, Yang J, Jiang C, Shen W, Wang L. Influence of angiogenin on the growth of A375 human melanoma cells and the expression of basic fibroblast growth factor. Melanoma Res. 2006 Apr;16(2):119-26 Jang SH, Song HD, Kang DK, Chang SI, Kim MK, Cho KH, Scheraga HA, Shin HC. Role of the surface loop on the structure and biological activity of angiogenin. BMB Rep. 2009 Dec 31;42(12):829-33 Tas F, Duranyildiz D, Oguz H, Camlica H, Yasasever V, Topuz E. Circulating serum levels of angiogenic factors and vascular endothelial growth factor receptors 1 and 2 in melanoma patients. Melanoma Res. 2006 Oct;16(5):405-11 Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet. 2009 Sep;41(9):1006-10 Yoshioka N, Wang L, Kishimoto K, Tsuji T, Hu GF. A therapeutic target for prostate cancer based on angiogeninstimulated angiogenesis and cancer cell proliferation. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14519-24 Yuan Y, Wang F, Liu XH, Gong DJ, Cheng HZ, Huang SD. Angiogenin is involved in lung adenocarcinoma cell proliferation and angiogenesis. Lung Cancer. 2009 Oct;66(1):28-36 Kawada M, Inoue H, Arakawa M, Takamoto K, Masuda T, Ikeda D. Highly tumorigenic human androgen receptor-positive prostate cancer cells overexpress angiogenin. Cancer Sci. 2007 Mar;98(3):350-6 Gessner C, Rechner B, Hammerschmidt S, Kuhn H, et al. Angiogenic markers in breath condensate identify non-small cell lung cancer. Lung Cancer. 2010 May;68(2):177-84 Kim HM, Kang DK, Kim HY, Kang SS, Chang SI. Angiogenininduced protein kinase B/Akt activation is necessary for angiogenesis but is independent of nuclear translocation of angiogenin in HUVE cells. Biochem Biophys Res Commun. 2007 Jan 12;352(2):509-13 This article should be referenced as such: Shimoyama S. ANG (angiogenin, ribonuclease, RNase A family, 5). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3):244-251. Kim SW, Kim JW, Kim YT, Kim JH, Kim S, Yoon BS, Nam EJ, Kim HY. Analysis of chromosomal changes in serous ovarian carcinoma using high-resolution array comparative genomic hybridization: Potential predictive markers of chemoresistant disease. Genes Chromosomes Cancer. 2007 Jan;46(1):1-9 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 251