SET (SET nuclear oncogene)

2013-05-01   Rebeca Manso-Alonso  

Pathology Department, Translational Oncology Division, IIS Fundacion Jimenez Diaz, E-28040 Madrid, Spain

Identity

HGNC
LOCATION
9q34.11
LOCUSID
ALIAS
2PP2A,I2PP2A,IGAAD,IPP2A2,MRD58,PHAPII,TAF-I,TAF-IBETA
FUSION GENES

DNA/RNA

Description

The SET gene spans 6.81 kb on the genomic DNA. The gene includes 8 exons.

Transcription

There are four transcript variants: 2863 bp (variant a); 2936 bp (variant b); 2638 bp (variant c); 2562 bp (variant d).

Proteins

Description

The SET protein is a potent endogenous inhibitor of protein phosphatase 2A (PP2A) that encodes three alternative isoforms; isoform 1 (TAF1 alpha)-290 amino acids, 33.5 kDa; isoform 2 (TAF1 beta) - 277 amino acids, 32 kDa ; isoform 3 - 265 amino acids, 31 kDa.

Expression

SET is expressed in a wide variety of tissues such as liver, kidney, pancreas, lung, uterus, muscle, brain, bladder and cochlea. Additionally, SET is overexpressed in numerous cancer types such as AUL (von Lindern et al., 1992), Wilms tumor (Carlson et al., 1998), T-ALL (Quentmeier et al., 2009), B-CLL and B-NHL (Christensen et al., 2011), and AML (Cristóbal et al., 2012).

Localisation

SET localizes predominantly in the nucleus; in the cytoplasm, it is found both in the cytosol and associated with the endoplasmic reticulum and with plasmatic membrane.

Function

SET is a multitasking protein involved in multiple cellular processes.
Role in apoptosis: SET oncogene inhibits the tumor suppressor NM23-H1, a Granzyme A-activated DNase during CTL-Mediated Apoptosis (Fan et al., 2003). Its role in apoptosis depends on the cellular model since while overexpression of SET induces neuronal apoptosis (Madeira et al., 2005), in AML resulted in decreased caspase-dependent apoptosis (Cristóbal et al., 2012).
Role in cell cycle: Overexpression of SET blocks the cell cycle at the G2/M transition in the colorrectal cancer cell line HCT116, inhibiting cyclin B-CDK1 activity in these cells. SET did not inhibit either cyclin A-CDK2 or cyclin E-CDK2 complexes. Moreover, SET and p21Cip1 cooperate in the inhibition of cyclin B-CDK1 activity (Canela et al., 2003).
Role in migration: SET stimulates cell migration in a Rac1-dependent manner. In fact, reduction of SET inhibits Rac1-induced migration, indicating that efficient Rac1 signaling requires membrane recruitment of SET (ten Klooster et al., 2007). A novel peptide antagonist of SET (COG112) inhibits SET association with Rac1 leading to decreased cellular migration and invasion (Switzer et al., 2011).
Role in nucleosome assembly: SET plays a role in MCPH1-mediated chromosome condensation/decondensation. SET inhibits PCAF-mediated acetylation of histones. In addition, SET also inhibits the histone acetyl transferases CREBBP and EP300. Besides, overexpression of SET has also been shown to inhibit demethylation of ectopically methylated DNA resulting in gene silencing (Cervoni et al., 2002).
Role in regulating AP-1 activity: Expression of SET in HEK-293 cells increased levels and DNA binding of c-Jun as well as the transcriptional activity of AP-1 (Al-Murrani et al., 1999).
Role in neuronal development: SET is a negative regulator of neuronal development (Kim et al., 2010) and it is involved in the pathogenesis of primary microcephaly (Leung et al., 2011) and Alzheimers disease (AD) (Madeira et al., 2005).

Homology

Belongs to the nucleosome assembly protein (NAP) family.

Implicated in

Entity name
Disease
Acute undifferentiated leukemia (AUL); only one case described so far.
Cytogenetics
Normal karyotype; may be overlooked.
Hybrid gene
5 SET - 3 NUP214.
Fusion protein
The SET-NUP214 (alias CAN) fusion protein consists of almost the whole SET protein fused to the C-terminus of NUP214.
Oncogenesis
SET-NUP214 leads to disorganization of nuclear export.
Entity name
Chronic and acute leukemias
Oncogenesis
Acute leukemias are very heterogeneous clonal diseases that disrupt normal hematopoiesis. SET is a reported oncoprotein with a preferentially nuclear location that has been shown to be fused to a putative oncoprotein, CAN/NUP214, in different types of leukemias. The SET-NUP214 (alias CAN) fusion protein consist of almost the whole SET protein fused to the C-terminus of NUP214 (5 SET - 3 NUP214). The fusion gene SET-NUP214 has been reported so far in a patient with acute undifferentiated leukemia (AUL) and normal karyotipe, in T-cell acute lymphoblastic leukemia (T-ALL) (von Lindern et al., 1992) and in one case of acute myeloid leukemia (AML) (Quentmeier et al., 2009; Chae et al., 2012). Functionally, it could promote an elevated expression of HOXA cluster genes in T-ALL. A pharmacologic SET antagonist (FTY720) has been found to induce apoptosis in T-ALL cells (Don et al., 2007; Wallington-Beddoe et al., 2011). Furthermore, overexpression of SET in AML promoted cell growth and resulted in decreased caspase-dependent apoptosis (Cristóbal I et al., 2012). Moreover, SET expression is elevated in B-cell chronic lymphocytic leukemia (CLL), and a SET antagonist peptide (COG449) has been reported to induce apoptosis in primary CLL cells (Christensen et al., 2011).
Entity name
B-cell non-Hodgkin lymphoma (NHL)
Oncogenesis
SET is significantly overexpressed in NHL cells relative to normal B cells (Christensen et al., 2011).
Entity name
Wilms tumor
Oncogenesis
High SET levels has been observed in Wilms tumor, but not in renal cell carcinoma, adult polycystic kidney disease or transitional cell carcinoma (Carlson et al., 1998).
Entity name
Alzheimers disease (AD)
Oncogenesis
SET protein specifically binds Jcasp early after internalization. Downregulation of SET reduces Jcasp-induced cell death, confirming a role of this protein in Jcasp induced apoptosis. However, overexpression of SET induces neuronal apoptosis, independently of Jcasp internalization, which suggests that SET level is crucial for neuronal survival/death (Madeira et al., 2005).
Entity name
Primary microcephaly
Oncogenesis
SET functions as a MCPH1-associated protein, negatively regulating chromosome condensation (Leung et al., 2011). SET expression shows variability throughout the cell cycle and is markedly reduced in the G2 phase, which coincides with Cdk1 activation (Brautigan et al., 1990). SET has also been suggested to be a negative regulator of mitotic entry by blocking cyclin B-CDK1 (Canela et al., 2003). Moreover, SET also binds to histones protecting them from acetylation by acetyltransferases, and this function may contribute to the potencial role of SET in regulating chromatin compaction and transcription (Cervoni et al., 2002).
Entity name
Lung cancer
Oncogenesis
SET is highly expressed in lung tumors. It has been reported that the FTY720-mediated necroptosis and lung tumor suppression involves SET and the kinase domain of RIPK1 (Saddoughi et al., 2013).

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 6418
MIM: 600960
HGNC: 10760
Ensembl: ENSG00000119335

Variants:

dbSNP: 6418
ClinVar: 6418
TCGA: ENSG00000119335
COSMIC: SET

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000119335ENST00000322030Q01105
ENSG00000119335ENST00000322030A0A024R895
ENSG00000119335ENST00000372686Q01105
ENSG00000119335ENST00000372688A0A0C4DFV9
ENSG00000119335ENST00000372692Q01105
ENSG00000119335ENST00000372692Q5VXV3
ENSG00000119335ENST00000409104Q01105
ENSG00000119335ENST00000454747B2REB7

Expression (GTEx)

0
50
100
150
200
250
300
350
400

Pathways

PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
HuR (ELAVL1) binds and stabilizes mRNAREACTOMER-HSA-450520
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
M PhaseREACTOMER-HSA-68886
Mitotic ProphaseREACTOMER-HSA-68875
Condensation of Prophase ChromosomesREACTOMER-HSA-2299718

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
381417612024PP2A inhibitor SET promotes mTORC1 and Bmi1 signaling through Akt activation and maintains the colony-formation ability of cancer cells.0
382774542024PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells.0
383559372024Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis.0
385558402024USP7 interacts with and destabilizes oncoprotein SET.0
381417612024PP2A inhibitor SET promotes mTORC1 and Bmi1 signaling through Akt activation and maintains the colony-formation ability of cancer cells.0
382774542024PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells.0
383559372024Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis.0
385558402024USP7 interacts with and destabilizes oncoprotein SET.0
377374862023Whole exome sequencing and transcriptome analysis in two unrelated patients with novel SET mutations.0
377941342023HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma.0
377374862023Whole exome sequencing and transcriptome analysis in two unrelated patients with novel SET mutations.0
377941342023HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma.0
350760732022The protein level of the tumour-promoting factor SET is regulated by cell density.2
351565352022Role of SET oncoprotein in hepatocellular carcinoma: An immunohistochemical study.1
358438862022The E3 Ligase TRIM4 Facilitates SET Ubiquitin-Mediated Degradation to Enhance ER-α Action in Breast Cancer.6

Citation

Rebeca Manso-Alonso

SET (SET nuclear oncogene)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version: http://atlasgeneticsoncology.org/gene/42272/deep-insight-explorer/case-report-explorer/js/lib/tumors-explorer/

Historical Card

2005-08-01 SET (SET nuclear oncogene) by  Sabine Strehl 

Childrens Cancer Research Institute, Kinderspitalgasse 6, A-1090 Vienna, Austria