Download Gene Section ANG (angiogenin, ribonuclease, RNase A family, 5)

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