RNF7 (RING finger protein-7)

2007-11-01 Yi Sun Affiliation

Department of Radiation Oncology, University of Michigan, 4304 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010, USA

Identity

HGNC

RNF7

LOCATION

3q23

IMAGE

LEGEND

A) Location. B) Local order

LOCUSID

9616

ALIAS

CKBBP1,ROC2,SAG,rbx2

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The gene encoding RNF7/SAG consists of four exons and three introns.

Transcription

About 0.8 kb mRNA with 342 bp open reading frame; three alternative splicing variants; induced by redox compound, tumor promoter (TPA), and hypoxia.

Pseudogene

Two psuedogenes, SAGp1 and SAGp2.

Proteins

Description

113 amino acids; 14 kDa protein; contains a RING domain (Cys-X2-Cys-X9-39-Cys-X1-3-His-X2-3-Cys/His-X2-Cys-X4-48-Cys-X2-Cys) at the C-terminus (50-102); Subjected to CK2 phosphorylation at Thr-10.

Expression

Ubiquitously expressed with the highest expression in heart, skeleton muscle, and testis in humans.

Localisation

Both cytoplasm and nucleus

Function

1) In vitro test tube assays using purified protein showed that RNF7/SAG scavenges hydrogen peroxide at the expense of self oligomerization; has thiol-linked peroxidase activity; inhibits peroxynitrite-induced DNA damage. When complexed with the components of SCF E3 ubiquitin ligase, SAG has E3 ubiquitin ligase activity.
2) In cultured cells, SAG over-expression inhibits apoptosis induced by redox, nitric oxide, ischemia/hypoxia, neurotoxin, MPP, and UV-irradiation (unpublished data). SAG over-expression also promotes the S-phase entry and cell growth under serum starved conditions and inhibits TPA-induced neoplastic transformation. Silencing SAG expression by anti-sense or siRNA inhibits tumor cell growth, enhanced apoptosis induced by etoposide and TRAIL, and enhances TPA-induced neoplastic transformation.
3) In whole animals, SAG over-expression via injection of SAG expressing recombinant adenovirus protects mouse brain tissues from ischemia/hypoxia-induced damage. Targeted expression of SAG in mouse skin inhibits tumor formation at the early stage, but enhances tumor growth at the later stage in a SAG-transgenic DMBA-TPA carcinogenesis model.
4) In yeast, SAG is a growth essential gene whose targeted deletion causes death, which can be rescued by human SAG.

Homology

SAG is an evolutionarily conserved gene with 96% protein sequence identity between human and mouse, 70% identify between human and C-elegans and 50% between human and yeast. Two family members are found in human and mouse, four in Drosophila, three in C-elegans, one in Arabidopsis and in yeast.

Mutations

Germinal

Not known

Somatic

Not known

Implicated in

Entity name

lung and colon cancer

Disease

SAG/RNF7 over-expression was found in lung cancer and a subset of colon cancer tissues.

Prognosis

Lung cancer patients with SAG/RNF7 over-expression have a worse prognosis.

Oncogenesis

Targeted over-expression of SAG/RNF7 in mouse skin by K14 promoter inhibits tumor formation, but enhances tumor growth in DMBA-TPA-induced skin carcinogenesis.

Bibliography

Pubmed ID	Last Year	Title	Authors
12676540	2003	SAG attenuates apoptotic cell death caused by simulated ischaemia/reoxygenation in rat cardiomyocytes.	Chanalaris A et al
11255262	2001	Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation.	Duan H et al
10082581	1999	SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents.	Duan H et al
17846172	2007	SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IkappaB-alpha/NF-kappaB.	Gu Q et al
17440073	2007	SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation.	Gu Q et al
16874460	2007	CK2 phosphorylation of SAG at Thr10 regulates SAG stability, but not its E3 ligase activity.	He H et al
11255265	2001	Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth.	Huang Y et al
11999705	2002	Thiol-linked peroxidase activity of human sensitive to apoptosis gene (SAG) protein.	Kim SY et al
17240529	2007	SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling.	Kim SY et al
12565832	2003	Human sensitive to apoptosis gene protein inhibits peroxynitrite-induced DNA damage.	Kim SY et al
12748192	2003	Phosphorylation of threonine 10 on CKBBP1/SAG/ROC2/Rbx2 by protein kinase CKII promotes the degradation of IkappaBalpha and p27Kip1.	Kim YS et al
11668520	2001	Expression of the sensitive to apoptosis gene, SAG, as a prognostic marker in nonsmall cell lung cancer.	Sasaki H et al
10506102	1999	Alterations of SAG mRNA in human cancer cell lines: requirement for the RING finger domain for apoptosis protection.	Sun Y et al
11554450	2001	SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions.	Sun Y et al
10443936	1999	Expression, purification, and biochemical characterization of SAG, a ring finger redox-sensitive protein.	Swaroop M et al
11506706	2001	SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes.	Swaroop M et al
10851089	2000	Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation.	Swaroop M et al
17217622	2006	SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection.	Tan M et al
17828303	2008	SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation.	Tan M et al
16484044	2006	Regulation of nitric oxide-induced apoptosis by sensitive to apoptosis gene protein.	Yang ES et al
11488541	2001	Attenuation of ischemia-induced mouse brain injury by SAG, a redox-inducible antioxidant protein.	Yang GY et al

Other Information

Locus ID:

NCBI: 9616
MIM: 603863
HGNC: 10070
Ensembl: ENSG00000114125

Variants:

dbSNP: 9616
ClinVar: 9616
TCGA: ENSG00000114125
COSMIC: RNF7

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000114125	ENST00000273480	Q9UBF6
ENSG00000114125	ENST00000393000	Q9UBF6
ENSG00000114125	ENST00000477012	Q9UBF6
ENSG00000114125	ENST00000477393	F8WEU8
ENSG00000114125	ENST00000480908	Q9UBF6

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Ubiquitin mediated proteolysis	KEGG	ko04120
Ubiquitin mediated proteolysis	KEGG	hsa04120
ECS complex	KEGG	hsa_M00388
ECS complex	KEGG	M00388
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Class I MHC mediated antigen processing & presentation	REACTOME	R-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradation	REACTOME	R-HSA-983168

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20103673	2010	Validation of SAG/RBX2/ROC2 E3 ubiquitin ligase as an anticancer and radiosensitizing target.	53
17217622	2006	SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection.	48
17828303	2008	SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation.	47
22841784	2012	Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection.	46
24430184	2014	Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis.	37
18454945	2008	Regulation of heat shock-induced apoptosis by sensitive to apoptosis gene protein.	18
25216516	2014	SAG/RBX2 is a novel substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization.	15
26030842	2015	A fluorescent bimolecular complementation screen reveals MAF1, RNF7 and SETD3 as PCNA-associated proteins in human cells.	10
27910872	2016	SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation.	10
12748192	2003	Phosphorylation of threonine 10 on CKBBP1/SAG/ROC2/Rbx2 by protein kinase CKII promotes the degradation of IkappaBalpha and p27Kip1.	6

Citation

Yi Sun

RNF7 (RING finger protein-7)

Atlas Genet Cytogenet Oncol Haematol. 2007-11-01

Online version: http://atlasgeneticsoncology.org/gene/44108/rnf7