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PIAS proteins also play a key role in double-stranded break DNA repair.<ref name="PIAS 3 Function" /> Exposure to [[UV light]], [[chemicals]], and [[ionizing radiation]] can cause DNA damage, and the most detrimental type of DNA damage is a double-stranded break.<ref name="PIAS 3 Function" /> PIAS1, PIAS3, and PIAS4 have been shown to recruit proteins to the site of the damage and promote repair.<ref name="PIAS 3 Function">{{cite journal|last=Liu|first=S|coauthors=Fan, Z; Geng, Z; Zhang, H; Ye, Q; Jiao, S; Xu, X|title=PIAS3 promotes homology-directed repair and distal non-homologous end joining.|journal=Oncology letters|date=Oct 2013|volume=6|issue=4|pages=1045–1048|pmid=24137461}}</ref><ref name="PIAS1 and PIAS4 Function in DSB">{{cite journal|last=Galanty|first=Y|coauthors=Belotserkovskaya, R; Coates, J; Polo, S; Miller, KM; Jackson, SP|title=Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.|journal=Nature|date=Dec 17, 2009|volume=462|issue=7275|pages=935–9|pmid=20016603}}</ref>
PIAS proteins also play a key role in double-stranded break DNA repair.<ref name="PIAS 3 Function" /> Exposure to [[UV light]], [[chemicals]], and [[ionizing radiation]] can cause DNA damage, and the most detrimental type of DNA damage is a double-stranded break.<ref name="PIAS 3 Function" /> PIAS1, PIAS3, and PIAS4 have been shown to recruit proteins to the site of the damage and promote repair.<ref name="PIAS 3 Function">{{cite journal|last=Liu|first=S|coauthors=Fan, Z; Geng, Z; Zhang, H; Ye, Q; Jiao, S; Xu, X|title=PIAS3 promotes homology-directed repair and distal non-homologous end joining.|journal=Oncology letters|date=Oct 2013|volume=6|issue=4|pages=1045–1048|pmid=24137461}}</ref><ref name="PIAS1 and PIAS4 Function in DSB">{{cite journal|last=Galanty|first=Y|coauthors=Belotserkovskaya, R; Coates, J; Polo, S; Miller, KM; Jackson, SP|title=Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.|journal=Nature|date=Dec 17, 2009|volume=462|issue=7275|pages=935–9|pmid=20016603}}</ref>


Additionally, PIAS proteins are important transcriptional co-regulators of the [[JAK-STAT signaling pathway|JAK/STAT signaling pathway]]. Although the exact mechanism isn’t clear, PIAS1 and PIASy both inhibit STAT-1 signaling.<ref name="STAT1 Inhibition"/><ref name="PIASy co-repressor">{{cite journal|last=Liu|first=B|coauthors=Gross, M; ten Hoeve, J; Shuai, K|title=A transcriptional corepressor of Stat1 with an essential LXXLL signature motif.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Mar 13, 2001|volume=98|issue=6|pages=3203–7|pmid=11248056}}</ref> PIAS3 was found to specifically inhibit STAT-3 signaling after stimulation by [[Interleukin 6|IL-6]].<ref name="PIAS3 discovery" />
Additionally, PIAS proteins are important transcriptional co-regulators of the [[JAK-STAT signaling pathway|JAK/STAT signaling pathway]]. PIAS protein's interaction with STAT signaling requires [[tyrosine phosphorylation]] of STAT proteins<ref name="IL-6 Principles">{{cite journal|last=Heinrich|first=PC|coauthors=Behrmann, I; Haan, S; Hermanns, HM; Müller-Newen, G; Schaper, F|title=Principles of interleukin (IL)-6-type cytokine signalling and its regulation.|journal=The Biochemical journal|date=2003 Aug 15|volume=374|issue=Pt 1|pages=1-20|pmid=12773095}}</ref> . Additionally, PIAS1 binds preferentially to un-methylated STAT1<ref name="IL-6 Principles" /> . Although the exact mechanism isn’t clear, PIAS1 and PIASy both inhibit STAT-1 signaling.<ref name="STAT1 Inhibition"/><ref name="PIASy co-repressor">{{cite journal|last=Liu|first=B|coauthors=Gross, M; ten Hoeve, J; Shuai, K|title=A transcriptional corepressor of Stat1 with an essential LXXLL signature motif.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Mar 13, 2001|volume=98|issue=6|pages=3203–7|pmid=11248056}}</ref> PIAS3 was found to specifically inhibit STAT-3 signaling after stimulation by [[Interleukin 6|IL-6]].<ref name="PIAS3 discovery" />


==Potential applications in disease treatment==
==Potential applications in disease treatment==

Revision as of 03:29, 23 April 2014

Protein inhibitors of activated STAT (PIAS) proteins regulate transcription in mammals. Despite their name, they can either activate or repress transcription. Whether PIAS proteins activate or repress transcription depends on the gene being regulated, as well as their specific type of interaction as transcriptional co-regulators with at least 60 different proteins. In addition to regulating activated STAT, PIAS proteins regulate other transcription factors, including NF-κB and p53, among others. They promote mechanisms that regulate transcription, including acting as E3 SUMO-protein ligases.

The seven proteins that belong to the mammalian PIAS family are encoded by four genes: PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy). Apart from PIAS1, each gene encodes two protein isoforms. Homologues of PIAS proteins have been found in other eukaryotes, including Zimp/dPIAS in Drosophila melanogaster and zfPIAS4a in zebrafish. SIZ1 and SIZ2 were two homologues identified in yeast.

PIAS proteins may have implications in preventing many diseases, including cancer, autoimmune diseases, and obesity.

Discovery

The discovery of PIAS3 was first published in 1997. The discovery was made while the JAK-STAT pathway was being studied.[1] The discovery of other PIAS proteins, including PIAS1, PIASxα, PIASxβ, and PIASy, was published the following year.[2] The interaction between STATs and PIASs was characterized by the yeast two-hybrid assay.[1][2] PIAS proteins were named based on their ability to inhibit STAT. For example, PIAS1 inhibited STAT1,[2] and PIAS3 inhbited STAT3.[1]

When it was discovered that PIAS proteins did far more than simply inhibit STATs, it has been proposed that the PIAS acronym should stand for Pleiotropic Interactors Associated with SUMO based on their association with SUMO proteins.[3]

The discovery of PIASyE6- was published in 2004. It is an isoform of PIASy that doesn't contain exon 6.[4]

Types of PIAS proteins

PHD zinc finger domain of SIZ1
Main articles: PIAS1, PIAS2, PIAS3, and PIAS4

The table below lists the seven known proteins that belong to the mammalian PIAS protein family.[3][5] Due to alternative splicing, some PIAS protein-encoding genes encode multiple protein products called isoforms.[6]

Gene Encodes
PIAS1 PIAS1
PIAS2 (PIASx) PIASxα, PIASxβ
PIAS3 PIAS3, PIAS3L (also known as PIAS3β)
PIAS4 (PIASy) PIASy, PIASyE6-

Homologues

Structure

The domains (SAP, RLD, AD, S/T) and motifs (PINIT, SIM) found in most protein inhibitors of activated STAT (PIAS)

Four PIAS domains and two PIAS motifs have been identified. They include the N-terminal scaffold attachment factor-A/B, acinus and PIAS (SAP) domain, the Pro-Ile-Asn-Ile-Thr (PINIT) motif, the RING-finger-like zinc-binding domain (RLD), the highly acidic domain (AD), the SUMO-interacting motif (SIM), and the serine/threonine-rich C-terminal region (S/T).[3][5][11][12]

SAP domain

p53 binding domain of PIAS-1
p53 binding domain of PIAS-1.

The SAP domain is found in all PIAS proteins.[12] It is composed of four alpha helices.[13] It binds to areas of chromatin that are rich in adenine (A) and thymine (T). These A/T rich regions are known as matrix-attachment regions.[14] Once bound, the matrix-attachment regions anchor loops of chromatin to the nuclear matrix. The nuclear matrix is a structure within the nucleus where it is thought that transcription regulation takes place.[5][12] SAP also binds to p53.[13]

Each SAP domain contains an LXXLL amino acid motif.[12] L = leucine, and X = any amino acid. This motif is used to bind to nuclear receptors. Nuclear receptors are transcription factors that regulate transcription upon ligand binding.[15]

PINIT motif

The PINIT motif was discovered in PIAS3L, an isoform of PIAS3. PIAS proteins tend to go back and forth between the nucleus and cytosol as they carry out their activities. PINIT is needed to localize PIAS3 and PIAS3L to the nucleus.[16]

PIASy has a slight difference in its PINIT motif: leucine is in place of the second isoleucine (PINLT). Furthermore, the PINIT motif is not found in PIASy isoform PIASyE6-. This isoform, lacking exon 6, is still retained in the nucleus despite lacking the PINIT motif. The reason for this is unknown.[4]

RLD

The RING-finger-like zinc-binding domain is present in all PIAS proteins. RLD is essential for PIAS proteins to function as E3 SUMO-protein ligases. It is also needed for successful interaction with other proteins. Its three dimensional structure is thought to be similar to typical RING finger domains. It contains one histidine residue and five cysteine residues [3]

AD and SIM

The highly acidic domain, present in all PIAS proteins, contains a SIM motif.[12] The SIM motif may be needed for PIAS proteins to accurately recognize and interact with other SUMO proteins. However, it is not needed for E3 SUMO-protein ligase activity to occur.[3] The function of the highly acidic domain is unknown.[5]

S/T region

The S/T region is not found in all PIAS proteins. PIASy and PIASyE6- are the only members of the PIAS protein family that lack this region.[12] Furthermore, the length of this region varies among PIAS protein isoforms.[3] The function of the S/T region is unknown. [5]

PIAS protein regions
Name Abbreviation Function(s)
N-terminal scaffold attachment factor-A/B, acinus and PIAS domain SAP Binds to DNA matrix-attachment regions, proteins (i.e.: p53, nuclear receptors) [5][12][13][3]
Pro-Ile-Asn-Ile-Thr motif PINIT nuclear retention [16]
RING-finger-like zinc-binding domain RLD SUMOylation; interaction with other proteins [3]
Highly acidic domain AD unknown [5]
SUMO-interacting motif SIM recognition and interaction with SUMO proteins [3]
Serine/threonine-rich C-terminal region S/T unknown [5]
Structural differences between PIAS proteins
Type[3][5] Amino acid length[3] Protein regions[3][5]
PIAS1 651 SAP, PINIT, RLD, AD, SIM, S/T
PIASxα 572 SAP, PINIT, RLD, AD, SIM, S/T
PIASxβ 621 SAP, PINIT, RLD, AD, SIM, S/T
PIAS3 593 SAP, PINIT, RLD, AD, SIM, S/T
PIAS3L 628 SAP, PINIT, RLD, AD, SIM, S/T
PIASy 510 SAP, PINIT, RLD, AD
PIASyE6- 467 SAP, RLD, AD

Functions

PIAS proteins contribute to the control of gene expression, and may be considered transcriptional co-regulators.[17] While PIAS proteins interact with at least 60 different proteins involved in transcription,[12] they are known to act as small ubiquitin-related modifiers (SUMOs).[17] Depending on the target gene or transcriptional co-regulator, PIAS proteins can be activators or repressors.[17] One function of PIAS proteins is to relocate transcriptional regulators to different compartments within the nucleus of the cell.[17]

PIAS proteins also play a key role in double-stranded break DNA repair.[18] Exposure to UV light, chemicals, and ionizing radiation can cause DNA damage, and the most detrimental type of DNA damage is a double-stranded break.[18] PIAS1, PIAS3, and PIAS4 have been shown to recruit proteins to the site of the damage and promote repair.[18][19]

Additionally, PIAS proteins are important transcriptional co-regulators of the JAK/STAT signaling pathway. PIAS protein's interaction with STAT signaling requires tyrosine phosphorylation of STAT proteins[20] . Additionally, PIAS1 binds preferentially to un-methylated STAT1[20] . Although the exact mechanism isn’t clear, PIAS1 and PIASy both inhibit STAT-1 signaling.[2][21] PIAS3 was found to specifically inhibit STAT-3 signaling after stimulation by IL-6.[1]

Potential applications in disease treatment

Defects in the DNA repair system lead to a predisposition for developing cancer. At least some of the PIAS proteins are implicated in DNA repair, and specifically in enhancing repair of double-stranded breaks. In cell culture, overexpression of PIAS3 demonstrated an increase resistance of HeLa cells to ionizing radiation.[18] This indicates a significant role for PIAS3 in DNA repair.[18] Additionally, overexpression of PIAS3 inhibited human lung cancer cell growth in vitro and rendered cancer cells up to 12X more sensitive to chemotherapeutic drugs.[22] While inhibition of PIAS by siRNAs led cancer cells to accelerate cell proliferation and demonstrate higher levels of resistance to chemotherapy drugs. In a study of human brain tissue samples from glioblastoma multiforme patients, PIAS3 expression was found to be reduced compared to the control brain tissue.[23] Inhibition of PIAS3 resulted in increased glioblastoma propagation, while PIAS3 overexpression inhibited STAT-3 signaling and cell proliferation . Furthermore, patients with higher levels of BRCA1, PIAS1, and PIAS4 survived for a longer period of time in a retrospective study of advanced gastric cancer patients.[24]

Given the preliminary evidence, PIAS proteins may be interesting targets for the development of treatments for cancers or as sensitizers for chemotherapeutic drugs and radiation in BRCA-deficient cancers.[18][22]

See also

References

  1. ^ a b c d Chung, CD (Dec 5, 1997). "Specific inhibition of Stat3 signal transduction by PIAS3". Science (New York, N.Y.). 278 (5344): 1803–5. PMID 9388184. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ a b c d Liu, B (Sep 1, 1998). "Inhibition of Stat1-mediated gene activation by PIAS1". Proceedings of the National Academy of Sciences of the United States of America. 95 (18): 10626–31. PMID 9724754. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ a b c d e f g h i j k l Rytinki, Miia M. (13 June 2009). "PIAS proteins: pleiotropic interactors associated with SUMO". Cellular and Molecular Life Sciences. 66 (18): 3029–3041. doi:10.1007/s00018-009-0061-z. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ a b Wong, KA (Jun 2004). "Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life". Molecular and cellular biology. 24 (12): 5577–86. PMID 15169916. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ a b c d e f g h i j Shuai, Ke (August 2005). "Regulation of gene-activation pathways by PIAS proteins in the immune system". Nature Reviews Immunology. 5 (8): 593–605. doi:10.1038/nri1667. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ University, James D. Watson, Cold Spring Harbor Laboratory, Tania A. Baker, Massachusetts Institute of Technology, Alexander Gann, Cold Spring Harbor Laboratory, Michael Levine, University of California, Berkeley, Richard Losik, Harvard (2014). Molecular biology of the gene (Seventh edition ed.). Boston: Pearson/CSH Press. p. 469. ISBN 0321762436. {{cite book}}: |edition= has extra text (help)CS1 maint: multiple names: authors list (link)
  7. ^ Mohr, SE (1999 Mar 18). "Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster". Gene. 229 (1–2): 109–16. PMID 10095110. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Betz, A (2001 Aug 14). "A Drosophila PIAS homologue negatively regulates stat92E". Proceedings of the National Academy of Sciences of the United States of America. 98 (17): 9563–8. PMID 11504941. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Xiong, R. (17 February 2012). "Characterization of a PIAS4 Homologue from Zebrafish: Insights into Its Conserved Negative Regulatory Mechanism in the TRIF, MAVS, and IFN Signaling Pathways during Vertebrate Evolution". The Journal of Immunology. 188 (6): 2653–2668. doi:10.4049/​jimmunol.1100959. PMID 22345667. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); zero width space character in |doi= at position 9 (help)
  10. ^ Johnson, ES (2001 Sep 21). "An E3-like factor that promotes SUMO conjugation to the yeast septins". Cell. 106 (6): 735–44. PMID 11572779. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Palvimo, J.J. (1 December 2007). "PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription". Biochemical Society Transactions. 35 (6): 1405. doi:10.1042/BST0351405.
  12. ^ a b c d e f g h Shuai, Ke (February 2006). "Regulation of cytokine signaling pathways by PIAS proteins". Cell Research. 16 (2): 196–202. doi:10.1038/sj.cr.7310027.
  13. ^ a b c Okubo, S. (8 May 2004). "NMR Structure of the N-terminal Domain of SUMO Ligase PIAS1 and Its Interaction with Tumor Suppressor p53 and A/T-rich DNA Oligomers". Journal of Biological Chemistry. 279 (30): 31455–31461. doi:10.1074/jbc.M403561200.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Aravind, L (Mar 2000). "SAP - a putative DNA-binding motif involved in chromosomal organization". Trends in biochemical sciences. 25 (3): 112–4. PMID 10694879. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  15. ^ Glass, CK (Jan 15, 2000). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes & development. 14 (2): 121–41. PMID 10652267. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ a b Duval, D (Nov 6, 2003). "The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L". FEBS letters. 554 (1–2): 111–8. PMID 14596924. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ a b c d Sharrocks, A. D. (17 March 2006). "PIAS proteins and transcriptional regulation--more than just SUMO E3 ligases?". Genes & Development. 20 (7): 754–758. doi:10.1101/gad.1421006.
  18. ^ a b c d e f Liu, S (Oct 2013). "PIAS3 promotes homology-directed repair and distal non-homologous end joining". Oncology letters. 6 (4): 1045–1048. PMID 24137461. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  19. ^ Galanty, Y (Dec 17, 2009). "Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks". Nature. 462 (7275): 935–9. PMID 20016603. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ a b Heinrich, PC (2003 Aug 15). "Principles of interleukin (IL)-6-type cytokine signalling and its regulation". The Biochemical journal. 374 (Pt 1): 1–20. PMID 12773095. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ Liu, B (Mar 13, 2001). "A transcriptional corepressor of Stat1 with an essential LXXLL signature motif". Proceedings of the National Academy of Sciences of the United States of America. 98 (6): 3203–7. PMID 11248056. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  22. ^ a b Ogata, Y (Oct 2006). "Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation". Neoplasia (New York, N.Y.). 8 (10): 817–25. PMID 17032498. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  23. ^ Brantley, EC (Aug 1, 2008). "Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression". Clinical cancer research : an official journal of the American Association for Cancer Research. 14 (15): 4694–704. PMID 18676737. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  24. ^ Wei, J (Oct 19, 2011). "mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer". Journal of the National Cancer Institute. 103 (20): 1552–6. PMID 21862729. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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