Open Access

Meta-analysis of SUMO1

BMC Research Notes20081:60

DOI: 10.1186/1756-0500-1-60

Received: 12 May 2008

Accepted: 31 July 2008

Published: 31 July 2008

Abstract

An abundantly growing body of literature implicates conjugation of SUMO in the regulation of many proteins and processes, yet the regulation of SUMO pathways is poorly understood. To gain insight into the players in the SUMO1 pathway I have performed an in-silico co-expression meta-analysis of SUMO1, comparing many different multi-microarray studies of various normal and human tumour tissues, from the Oncomine database. This serves as a data-driven predictor of pathway partners of SUMO1. While the data obtained need to be confirmed by future independent experiments and can currently only be considered a hypothesis, results implicate defender against cell death (DAD1) and the anti-apoptotic DEK oncogene as new pathway partners of SUMO1.

Discussion

Oncomine [1] meta-analysis was performed as previously described [2, 3]. Briefly, 15 multi-array studies were analyzed for common overlapping co-expressed genes of SUMO1, using muti-array studies within the Oncomine integrated cancer database. This technique gives insight into which pathways the searched gene (in this case SUMO1) are involved in, although it is impossible to tell if co-expressed gene products are complexed to SUMO1, act upstream of SUMO1 or downstream of SUMO1. Therefore, while limited, this technique is important for generating leads to assess both the pathways SUMO1 is important for, and regulation of SUMO1 itself.

After meta-analysis there were over 400 consistently co-expressed genes at the cutoff of 3 studies (Additional File 1). Table 1 shows the genes with the higher cutoff of 4 studies. This high number may be expected as SUMO1 is a general factor and involved in many processes. I note that the archetype SUMO1-modified promyelocytic leukemia (PML) was co-expressed with SUMO1, acting as validation of the results [4]. While the Ubc9 conjugation enzyme was not found to be co-expressed many other ubiquitin-conjugating enzymes were (UBE2N, UBE4A, UBE2G1, UBE2V2, UBE2E1, UBE2D2, UBE2A, UBE1C, CUL4A), as was the SUMO1 activating enzyme subunit 2 (UBA2). Transcription factors shown to be modified by SUMO were also co-expressed, such as HIF1α, Rb, YY1, and SMAD4 [59]. Interestingly RARα is also co-expressed and while it has never been shown to be a target of SUMO1 the PML-RARα fusion has been shown to be a target of SUMO1 mediated degradation [10]. It would be interesting to investigate if RARα itself is a SUMO1 target. Also co-expressed is the NF-κB subunit RelA. While RelA also is not a proven target of SUMO1 NF-κB is regulated indirectly by SUMO1 modification of Iκ Kgamma/NEMO or IκB [11, 12].
Table 1

Oncomine meta-analysis of SUMO1 co-expressed genes

GENE

%

GENE NAME

SUMO1

100%

SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae)

DAD1

67%

defender against cell death 1

DEK

53%

DEK oncogene (DNA binding)

UBE2N

47%

ubiquitin-conjugating enzyme E2N (UBC13 homolog, yeast)

SET

47%

SET translocation (myeloid leukemia-associated)

SLC25A5

40%

solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 5

SFRS3

40%

splicing factor, arginine/serine-rich 3

RPA1

40%

replication protein A1, 70 kDa

RCN2

40%

Reticulocalbin 2, EF-hand calcium binding domain

RB1

40%

retinoblastoma 1 (including osteosarcoma)

PSMD14

40%

proteasome (prosome, macropain) 26S subunit, non-ATPase, 14

PSMC2

40%

proteasome (prosome, macropain) 26S subunit, ATPase, 2

PSMA2

40%

proteasome (prosome, macropain) subunit, alpha type, 2

NUP153

40%

nucleoporin 153 kDa

GLO1

40%

glyoxalase I

DPM1

40%

dolichyl-phosphate mannosyltransferase polypeptide 1, catalytic subunit

DARS

40%

Aspartyl-tRNA synthetase

CD164

40%

CD164 antigen, sialomucin

CCT8

40%

chaperonin containing TCP1, subunit 8 (theta)

BNIP2

40%

BCL2/adenovirus E1B 19 kDa interacting protein 2

YY1

33%

YY1 transcription factor

VPS16

33%

vacuolar protein sorting 16 (yeast)

USP1

33%

ubiquitin specific protease 1

UBE4A

33%

ubiquitination factor E4A (homologous to yeast UFD2)

UBE2G1

33%

ubiquitin-conjugating enzyme E2G 1 (UBC7 homolog, C. elegans)

TSNAX

33%

translin-associated factor X

SSBP1

33%

single-stranded DNA-binding protein 1

SMAD4

33%

SMAD, mothers against DPP homolog 4 (Drosophila)

SIAHBP1

33%

siah binding protein 1

SEC61B

33%

Sec61 beta subunit

RIF1

33%

RAP1 interacting factor homolog (yeast)

RBMX

33%

RNA binding motif protein, X-linked

PSMA3

33%

proteasome (prosome, macropain) subunit, alpha type, 3

PPP6C

33%

protein phosphatase 6, catalytic subunit

POLD2

33%

polymerase (DNA directed), delta 2, regulatory subunit 50 kDa

NCBP2

33%

nuclear cap binding protein subunit 2, 20 kDa

IRS1

33%

insulin receptor substrate 1

ILF3

33%

interleukin enhancer binding factor 3, 90 kDa

HMGN4

33%

high mobility group nucleosomal binding domain 4

H2AFV

33%

H2A histone family, member V

G22P1

33%

thyroid autoantigen 70 kDa (Ku antigen)

EIF2S3

33%

eukaryotic translation initiation factor 2, subunit 3 gamma, 52 kDa

CUL1

33%

cullin 1

C10orf7

33%

chromosome 10 open reading frame 7

BZW1

33%

basic leucine zipper and W2 domains 1

BRD2

33%

bromodomain-containing 2

ATP6V0B

33%

ATPase, H+ transporting, lysosomal 21 kDa, V0 subunit c'

ATP5J

33%

ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F6

WEE1

27%

WEE1 homolog (S. pombe)

VBP1

27%

von Hippel-Lindau binding protein 1 (prefoldin 3)

UQCRC1

27%

ubiquinol-cytochrome c reductase core protein I

UBXD2

27%

UBX domain containing 2

TSN

27%

translin

TNIP1

27%

TNFAIP3 interacting protein 1

TEBP

27%

unactive progesterone receptor, 23 kD

TAX1BP3

27%

Tax1 (human T-cell leukemia virus type I) binding protein 3

TANK

27%

TRAF family member-associated NFKB activator

SYPL

27%

synaptophysin-like protein

SUPT6H

27%

suppressor of Ty 6 homolog (S. cerevisiae)

SUPT5H

27%

suppressor of Ty 5 homolog (S. cerevisiae)

SUCLG1

27%

succinate-CoA ligase, GDP-forming, alpha subunit

SRI

27%

sorcin

SON

27%

SON DNA binding protein

SNRPD3

27%

small nuclear ribonucleoprotein D3 polypeptide 18 kDa

SNAP23

27%

synaptosomal-associated protein, 23 kDa

SMAP

27%

small acidic protein

S100A11

27%

S100 calcium binding protein A11 (calgizzarin)

RW1

27%

RW1 protei

RSN

27%

restin (Reed-Steinberg cell-expressed intermediate filament-associated protein)

RPL36AL

27%

ribosomal protein L36a-like

RPA3

27%

replication protein A3, 14 kDa

RNF4

27%

ring finger protein 4

RBL2

27%

retinoblastoma-like 2 (p130)

RBBP4

27%

retinoblastoma binding protein 4

RARS

27%

arginyl-tRNA synthetase

RANBP2

27%

RAN binding protein 2

RAE1

27%

RAE1 RNA export 1 homolog (S. pombe)

RAB1A

27%

RAB1A, member RAS oncogene family

PXMP3

27%

peroxisomal membrane protein 3, 35 kDa (Zellweger syndrome)

PTPN12

27%

protein tyrosine phosphatase, non-receptor type 12

PTMA

27%

prothymosin, alpha (gene sequence 28)

PSMA5

27%

proteasome (prosome, macropain) subunit, alpha type, 5

PSMA4

27%

proteasome (prosome, macropain) subunit, alpha type, 4

PRKDC

27%

protein kinase, DNA-activated, catalytic polypeptide

PML

27%

promyelocytic leukemia

PHKB

27%

phosphorylase kinase, beta

NOLC1

27%

nucleolar and coiled-body phosphoprotein

MUC2

27%

mucin 2, intestinal/tracheal

MPI

27%

mannose phosphate isomerase

MGAT1

27%

mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase

MCP

27%

membrane cofactor protein (CD46, trophoblast-lymphocyte cross-reactive antigen)

MARK3

27%

MAP/microtubule affinity-regulating kinase 3

MARK2

27%

MAP/microtubule affinity-regulating kinase 2

MARCKS

27%

myristoylated alanine-rich protein kinase C substrate

MAP2K3

27%

mitogen-activated protein kinase kinase 3

LIMK2

27%

LIM domain kinase 2

LEREPO4

27%

likely ortholog of mouse immediate early response, erythropoietin 4

KPNA2

27%

karyopherin alpha 2 (RAG cohort 1, importin alpha 1)

KIAA0092

27%

translokin

IL13RA1

27%

interleukin 13 receptor, alpha 1

HSPE1

27%

heat shock 10 kDa protein 1 (chaperonin 10)

HNRPA0

27%

heterogeneous nuclear ribonucleoprotein A0

HMGN3

27%

high mobility group nucleosomal binding domain 3

HLA-A

27%

major histocompatibility complex, class I, A

HIF1A

27%

hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)

HAT1

27%

histone acetyltransferase 1

HADHA

27%

hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A

  

thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit

GTF3C2

27%

general transcription factor IIIC, polypeptide 2, beta 110 kDa

GRSF1

27%

G-rich RNA sequence binding factor 1

GA17

27%

dendritic cell protein

G3BP

27%

Ras-GTPase-activating protein SH3-domain-binding protein

FUBP3

27%

far upstream element (FUSE) binding protein 3

FMR1

27%

fragile × mental retardation 1

FKBP1A

27%

FK506 binding protein 1A, 12 kDa

FDFT1

27%

farnesyl-diphosphate farnesyltransferase 1

FAM3C

27%

family with sequence similarity 3, member C

EWSR1

27%

Ewing sarcoma breakpoint region 1

EPS8

27%

epidermal growth factor receptor pathway substrate 8

EIF3S9

27%

eukaryotic translation initiation factor 3, subunit 9 eta, 116 kDa

EFNA1

27%

ephrin-A1

DYRK1A

27%

dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A

DLG1

27%

DLG1

DDOST

27%

dolichyl-diphosphooligosaccharide-protein glycosyltransferase

DCTN6

27%

dynactin 6

DBI

27%

diazepam binding inhibitor (GABA receptor modulator, acyl-Coenzyme A binding)

DAZAP2

27%

DAZ associated protein 2

DAG1

27%

dystroglycan 1 (dystrophin-associated glycoprotein 1)

CUL4A

27%

cullin 4A

CSPG6

27%

chondroitin sulfate proteoglycan 6 (bamacan)

COG2

27%

component of oligomeric golgi complex 2

CEBPD

27%

CCAAT/enhancer binding protein (C/EBP), delta

CDC34

27%

cell division cycle 34

CD9

27%

CD9 antigen (p24)

CCT6A

27%

chaperonin containing TCP1, subunit 6A (zeta 1)

CBX3

27%

chromobox homolog 3 (HP1 gamma homolog, Drosophila)

CARS

27%

cysteinyl-tRNA synthetase

C1D

27%

nuclear DNA-binding protein

C14orf32

27%

chromosome 14 open reading frame 32

BUB3

27%

BUB3 budding uninhibited by benzimidazoles 3 homolog (yeast)

BSG

27%

basigin (OK blood group)

BLOC1S1

27%

biogenesis of lysosome-related organelles complex-1, subunit 1

BIRC2

27%

baculoviral IAP repeat-containing 2

ARMC2

27%

armadillo repeat containing 2

ANP32A

27%

acidic (leucine-rich) nuclear phosphoprotein 32 family, member A

Oncomine meta-analysis of SUMO1 co-expressed genes at a cutoff of 27% overlap (4 studies).

A similar meta-analysis was attempted for SUMO2 and SUMO3. However, SUMO2 was not expressed to levels that allowed for meta-analysis, and the results of SUMO3 meta-analysis gave fewer co-expressed genes than for SUMO1 (Additional File 2). There was a small overlap (37 genes) of co-expressed genes of SUMO1:SUMO3, but this does not necessarily imply that both are involved in completely distinct pathways. Rather, the meta-analysis technique has a high false-negative rate meaning that while the co-expressed genes we see are significant we will never get full coverage of every co-expressed gene as the stringency level of analysis is high.

SUMO1 was also seen to be involved in cell death pathways. In 67% (10 out of 15) of the studies analyzed SUMO1 was co-expressed with the defender against cell death (DAD1) gene. This was the highest co-expression with SUMO1 in the meta-analysis. As the name suggests DAD1 is anti-apoptotic and can be upregulated in cancer [13, 14]. Other SUMO1 co-expressed genes involved in cell death pathways include RELA, FADD, BCL2A1, BAK1, TNFRSF1A. The high co-expression with DAD1 is a novel finding and may prove important to SUMO1 pathways.

DEK oncogene was the next highest co-expressed gene (53%) with SUMO1. The DEK protein is important for chromatin structure, and may also play a role in cell death pathways by inhibiting apoptosis [1517].

While co-expression meta-analysis data has previously been shown to have a high correlation with known pathways in other studies [2, 3], prudence should still be used when interpreting novel findings until they can be proven in a separate experimental system. For this reason the meta-analysis list is presented here only as a predictive data-driven hypothesis. The next step is experimental analysis of DEK and DAD1 proteins to assess whether they are targets of SUMO1 conjugation, protein-complex partners of SUMO1, or act upstream or downstream of SUMO1.

In summary, it is interesting that both of the highest co-expressed genes of SUMO1 are anti-apoptotic, and it is tempting to speculate that this may be an important pathway of SUMO1 regulation.

Conclusion

Using co-expression meta-analysis from the Oncomine database SUMO1 co-expressed with many gene products, some which are already known to be in SUMO1 pathways. Novel predicted pathway partners include the DEK oncogene and DAD1, both of which co-expressed in over half of all studies analyzed. However, in what regard they take part in SUMO1 pathways remains to be further investigated.

Declarations

Acknowledgements

BW is funded by a McGill University Health Centre fellowship. I thank Annie Tremblay for helpful discussions.

Authors’ Affiliations

(1)
Molecular Oncology Group, Room H5-45, McGill University Health Centre

References

  1. Oncomine: [http://www.oncomine.org]
  2. Wilson BJ, Giguere V: Identification of novel pathway partners of p68 and p72 RNA helicases through Oncomine meta-analysis. BMC Genomics. 2007, 8: 419-10.1186/1471-2164-8-419.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Wilson BJ, Giguere V: Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway. Mol Cancer. 2008, 7: 49-10.1186/1476-4598-7-49.PubMed CentralView ArticlePubMedGoogle Scholar
  4. Muller S, Matunis MJ, Dejean A: Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. Embo J. 1998, 17: 61-70. 10.1093/emboj/17.1.61.PubMed CentralView ArticlePubMedGoogle Scholar
  5. Bae SH, Jeong JW, Park JA, Kim SH, Bae MK, Choi SJ, Kim KW: Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun. 2004, 324: 394-400. 10.1016/j.bbrc.2004.09.068.View ArticlePubMedGoogle Scholar
  6. Ledl A, Schmidt D, Muller S: Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor. Oncogene. 2005, 24: 3810-3818. 10.1038/sj.onc.1208539.View ArticlePubMedGoogle Scholar
  7. Deng Z, Wan M, Sui G: PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Mol Cell Biol. 2007, 27: 3780-3792. 10.1128/MCB.01761-06.PubMed CentralView ArticlePubMedGoogle Scholar
  8. Sternsdorf T, Jensen K, Will H: Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1. J Cell Biol. 1997, 139: 1621-1634. 10.1083/jcb.139.7.1621.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Lin X, Liang M, Liang YY, Brunicardi FC, Melchior F, Feng XH: Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4. J Biol Chem. 2003, 278: 18714-18719. 10.1074/jbc.M302243200.View ArticlePubMedGoogle Scholar
  10. Duprez E, Saurin AJ, Desterro JM, Lallemand-Breitenbach V, Howe K, Boddy MN, Solomon E, de The H, Hay RT, Freemont PS: SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation. J Cell Sci. 1999, 112 (Pt 3): 381-393.PubMedGoogle Scholar
  11. Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S: Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell. 2003, 115: 565-576. 10.1016/S0092-8674(03)00895-X.View ArticlePubMedGoogle Scholar
  12. Carbia-Nagashima A, Gerez J, Perez-Castro C, Paez-Pereda M, Silberstein S, Stalla GK, Holsboer F, Arzt E: RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell. 2007, 131: 309-323. 10.1016/j.cell.2007.07.044.View ArticlePubMedGoogle Scholar
  13. Hong NA, Flannery M, Hsieh SN, Cado D, Pedersen R, Winoto A: Mice lacking Dad1, the defender against apoptotic death-1, express abnormal N-linked glycoproteins and undergo increased embryonic apoptosis. Dev Biol. 2000, 220: 76-84. 10.1006/dbio.2000.9615.View ArticlePubMedGoogle Scholar
  14. Tanaka K, Kondoh N, Shuda M, Matsubara O, Imazeki N, Ryo A, Wakatsuki T, Hada A, Goseki N, Igari T, Hatsuse K, Aihara T, Horiuchi S, Yamamoto N, Yamamoto M: Enhanced expression of mRNAs of antisecretory factor-1, gp96, DAD1 and CDC34 in human hepatocellular carcinomas. Biochim Biophys Acta. 2001, 1536: 1-12.View ArticlePubMedGoogle Scholar
  15. Waldmann T, Scholten I, Kappes F, Hu HG, Knippers R: The DEK protein – an abundant and ubiquitous constituent of mammalian chromatin. Gene. 2004, 343: 1-9. 10.1016/j.gene.2004.08.029.View ArticlePubMedGoogle Scholar
  16. Cleary J, Sitwala KV, Khodadoust MS, Kwok RP, Mor-Vaknin N, Cebrat M, Cole PA, Markovitz DM: p300/CBP-associated factor drives DEK into interchromatin granule clusters. J Biol Chem. 2005, 280: 31760-31767. 10.1074/jbc.M500884200.View ArticlePubMedGoogle Scholar
  17. Wise-Draper TM, Allen HV, Jones EE, Habash KB, Matsuo H, Wells SI: Apoptosis inhibition by the human DEK oncoprotein involves interference with p53 functions. Mol Cell Biol. 2006, 26: 7506-7519. 10.1128/MCB.00430-06.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Wilson; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement