SET (SET nuclear oncogene)

2013-05-01   Rebeca Manso-Alonso 

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





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


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



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.


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).


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.


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).


Belongs to the nucleosome assembly protein (NAP) family.

Implicated in

Entity name
Acute undifferentiated leukemia (AUL); only one case described so far.
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.
SET-NUP214 leads to disorganization of nuclear export.
Entity name
Chronic and acute leukemias
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)
SET is significantly overexpressed in NHL cells relative to normal B cells (Christensen et al., 2011).
Entity name
Wilms tumor
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)
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
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
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).


Pubmed IDLast YearTitleAuthors
82944831994Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia.Adachi Y et al
103930851999Expression of I2PP2A, an inhibitor of protein phosphatase 2A, induces c-Jun and AP-1 activity.Al-Murrani SW et al
24066141990Cell cycle oscillation of phosphatase inhibitor-2 in rat fibroblasts coincident with p34cdc2 restriction.Brautigan DL et al
124071072003The SET protein regulates G2/M transition by modulating cyclin B-cyclin-dependent kinase 1 activity.Canela N et al
97737881998Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor.Carlson SG et al
119787942002The oncoprotein Set/TAF-1beta, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing.Cervoni N et al
217207442012Phenotypic and genetic characterization of adult T-cell acute lymphoblastic leukemia with del(9)(q34);SET-NUP214 rearrangement.Chae H et al
199007562010Decreased expression of microRNA-199b increases protein levels of SET (protein phosphatase 2A inhibitor) in human choriocarcinoma.Chao A et al
218445652011SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.Christensen DJ et al
221337792012Overexpression of SET is a recurrent event associated with poor outcome and contributes to protein phosphatase 2A inhibition in acute myeloid leukemia.Cristóbal I et al
174005552007Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues.Don AS et al
126281862003Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor.Fan Z et al
146716432004Effects of SET and SET-CAN on the differentiation of the human promonocytic cell line U937.Kandilci A et al
208005722010Negative regulation of neuronal cell differentiation by INHAT subunit SET/TAF-Iβ.Kim DW et al
221435342012Accumulation of the SET protein in HEK293T cells and mild oxidative stress: cell survival or death signaling.Leopoldino AM et al
215156712011SET nuclear oncogene associates with microcephalin/MCPH1 and regulates chromosome condensation.Leung JW et al
86266471996The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A.Li M et al
161628532005SET protein (TAF1beta, I2PP2A) is involved in neuronal apoptosis induced by an amyloid precursor protein cytoplasmic subdomain.Madeira A et al
77537971995Replication factor encoded by a putative oncogene, set, associated with myeloid leukemogenesis.Nagata K et al
191665872009SET-NUP214 fusion in acute myeloid leukemia- and T-cell acute lymphoblastic leukemia-derived cell lines.Quentmeier H et al
231805652013Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis.Saddoughi SA et al
152391262004Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export.Saito S et al
212976672011Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy.Switzer CH et al
214606332011FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells.Wallington-Beddoe CT et al
172454282007Rac1-induced cell migration requires membrane recruitment of the nuclear oncogene SET.ten Klooster JP et al
16304501992Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3' half to different genes: characterization of the set gene.von Lindern M et al

Other Information

Locus ID:

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


dbSNP: 6418
ClinVar: 6418
TCGA: ENSG00000119335


Gene IDTranscript IDUniprot

Expression (GTEx)



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
Mitotic ProphaseREACTOMER-HSA-68875
Condensation of Prophase ChromosomesREACTOMER-HSA-2299718

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
162862442005The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein.180
190288392009Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling.85
182994492008The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.70
173605162007Relationship between the structure of SET/TAF-Ibeta/INHAT and its histone chaperone activity.63
249275632014Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer.57
172454282007Rac1-induced cell migration requires membrane recruitment of the nuclear oncogene SET.52
212893142011Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A.51
183746432008Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase.50
175299932007SET and PARP1 remove DEK from chromatin to permit access by the transcription machinery.49
192344872009Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients.47


Rebeca Manso-Alonso

SET (SET nuclear oncogene)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version:

Historical Card

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

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