Protein inhibitor of activated STAT

{{Use dmy dates|date=December 2016}} [[File:Jakstat pathway PIAS.svg|thumb|right|x230px|PIAS and the JAK-STAT pathway. Upon stimulation by IL-6, PIAS3 can inhibit transcription activation by activated STAT3.]] '''Protein inhibitor of activated STAT''' ('''PIAS'''), also known as '''E3 SUMO-protein ligase PIAS''', is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with.

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 contain each conserved domain and motif of the PIAS protein family, with a few exceptions. The known functions of these domains and motifs are similar among all PIAS protein family members. These functions include acting as E3 SUMO-protein ligases during SUMOylation, which is an important process in transcriptional regulation. Presently, less is known about the higher order structure of PIAS proteins. The three-dimensional protein structures of PIAS2, PIAS3, and SIZ1 have only recently been solved.

PIAS proteins have potential applications in cancer treatment and prevention. They may also play an important role in regulating immune system responses.

== Discovery ==

The discovery of PIAS3 was first published in 1997. The discovery was made while the JAK-STAT pathway was being studied.<ref name="PIAS3 discovery">{{cite journal | vauthors = Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K | title = Specific inhibition of Stat3 signal transduction by PIAS3 | journal = Science | volume = 278 | issue = 5344 | pages = 1803–5 | date = December 1997 | pmid = 9388184 | doi = 10.1126/science.278.5344.1803 | bibcode = 1997Sci...278.1803C }}</ref> The discovery of other PIAS proteins, including PIAS1, PIASxα, PIASxβ, and PIASy, was published the following year.<ref name="STAT1 Inhibition">{{cite journal | vauthors = Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K | title = Inhibition of Stat1-mediated gene activation by PIAS1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 18 | pages = 10626–31 | date = September 1998 | pmid = 9724754 | pmc = 27945 | doi = 10.1073/pnas.95.18.10626 | bibcode = 1998PNAS...9510626L | doi-access = free }}</ref> The interaction between STATs and PIASs was characterized by the yeast two-hybrid assay.<ref name="PIAS3 discovery" /><ref name="STAT1 Inhibition" /> PIAS proteins were named based on their ability to inhibit STAT. For example, PIAS1 inhibited STAT1,<ref name="STAT1 Inhibition" /> and PIAS3 inhibited STAT3.<ref name="PIAS3 discovery" />

When it was discovered that PIAS proteins did far more than simply inhibit STATs, it was proposed that the PIAS acronym should stand for '''P'''leiotropic '''I'''nteractors '''A'''ssociated with '''S'''UMO based on their association with SUMO proteins.<ref name="SUMO interactions">{{cite journal | vauthors = Rytinki MM, Kaikkonen S, Pehkonen P, Jääskeläinen T, Palvimo JJ | title = PIAS proteins: pleiotropic interactors associated with SUMO | journal = Cellular and Molecular Life Sciences | volume = 66 | issue = 18 | pages = 3029–41 | date = September 2009 | pmid = 19526197 | doi = 10.1007/s00018-009-0061-z | s2cid = 5619331 | pmc = 11115825 }}</ref> Additionally, E3 SUMO-protein ligase PIAS is an alternative name for PIAS proteins.<ref name="alternate naming of PIAS">{{cite journal | vauthors = Van Itallie CM, Mitic LL, Anderson JM | title = SUMOylation of claudin-2 | journal = Annals of the New York Academy of Sciences | volume = 1258 | issue = 1 | pages = 60–4 | date = July 2012 | pmid = 22731716 | doi = 10.1111/j.1749-6632.2012.06541.x | url = https://zenodo.org/record/1230772 | bibcode = 2012NYASA1258...60V | s2cid = 45684330 }}</ref>

The discovery of PIAS3L, an isoform of PIAS3, was published in 2003.<ref name="PINIT discovery" /> In addition, the discovery of PIASyE6- was published in 2004. It is an isoform of PIASy that doesn't contain exon 6.<ref name="PINIT not in PIAS4E6-">{{cite journal | vauthors = Wong KA, Kim R, Christofk H, Gao J, Lawson G, Wu H | title = 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 | journal = Molecular and Cellular Biology | volume = 24 | issue = 12 | pages = 5577–86 | date = June 2004 | pmid = 15169916 | pmc = 419860 | doi = 10.1128/MCB.24.12.5577-5586.2004 }}</ref>

== Types of PIAS proteins ==

[[File:PDB 1wew EBI.jpg|thumb|PHD zinc finger domain of SIZ1. SIZ1 is a PIAS protein homologue found in yeast.]] {{Main|PIAS1|PIAS2|PIAS3|PIAS4}} The table below lists the seven known proteins that belong to the mammalian PIAS protein family.<ref name="SUMO interactions" /><ref name="PIAS overview Shuai">{{cite journal | vauthors = Shuai K, Liu B | title = Regulation of gene-activation pathways by PIAS proteins in the immune system | journal = Nature Reviews. Immunology | volume = 5 | issue = 8 | pages = 593–605 | date = August 2005 | pmid = 16056253 | doi = 10.1038/nri1667 | s2cid = 7466028 | doi-access = free }}</ref> Due to alternative splicing, some PIAS protein-encoding genes encode multiple protein products called isoforms.<ref name="Watson book">{{cite book|last=University|first=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|title=Molecular biology of the gene|year=2014|publisher=Pearson/CSH Press|location=Boston|isbn=978-0-321-76243-6|pages=469|edition=Seventh}}</ref> ''PIAS1'' is the only gene of this family that does not encode any isoforms.<ref name="SUMO interactions" />

{| class="wikitable collapsible" |- ! Gene !! Encoded Protein(s) |- | ''PIAS1'' || PIAS1 |- | ''PIAS2'' (''PIASx'') || PIASxα, PIASxβ |- | ''PIAS3'' || PIAS3, PIAS3L (also known as PIAS3β) |- | ''PIAS4'' (''PIASy'') || PIASy, PIASyE6- |}

=== Homologues ===

Homologues of PIAS proteins have been found in other eukaryotes, and several are listed below:

*Zimp/dPIAS in ''Drosophila melanogaster''<ref>{{cite journal | vauthors = Mohr SE, Boswell RE | title = Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster | journal = Gene | volume = 229 | issue = 1–2 | pages = 109–16 | date = March 1999 | pmid = 10095110 | doi = 10.1016/s0378-1119(99)00033-5 }}</ref><ref>{{cite journal | vauthors = Betz A, Lampen N, Martinek S, Young MW, Darnell JE | title = A Drosophila PIAS homologue negatively regulates stat92E | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 17 | pages = 9563–8 | date = August 2001 | pmid = 11504941 | pmc = 55492 | doi = 10.1073/pnas.171302098 | bibcode = 2001PNAS...98.9563B | doi-access = free }}</ref> *zfPIAS4a in zebrafish<ref name=zebrafish>{{cite journal | vauthors = Xiong R, Nie L, Xiang LX, Shao JZ | title = 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 | journal = Journal of Immunology | volume = 188 | issue = 6 | pages = 2653–68 | date = March 2012 | pmid = 22345667 | doi = 10.4049/jimmunol.1100959 | s2cid = 207425842 | doi-access = free }}</ref> *SIZ1 and SIZ2 in yeast<ref name=yeast>{{cite journal | vauthors = Johnson ES, Gupta AA | title = An E3-like factor that promotes SUMO conjugation to the yeast septins | journal = Cell | volume = 106 | issue = 6 | pages = 735–44 | date = September 2001 | pmid = 11572779 | doi = 10.1016/s0092-8674(01)00491-3 | s2cid = 14375183 | doi-access = free }}</ref><ref name="SIZ1 info">{{cite journal | vauthors = Takahashi Y, Kikuchi Y | title = Yeast PIAS-type Ull1/Siz1 is composed of SUMO ligase and regulatory domains | journal = The Journal of Biological Chemistry | volume = 280 | issue = 43 | pages = 35822–8 | date = October 2005 | pmid = 16109721 | doi = 10.1074/jbc.M506794200 | s2cid = 24493405 | doi-access = free }}</ref>

== Function ==

PIAS proteins contribute to the control of gene expression, and may be considered transcriptional co-regulators.<ref name="SUMO Function">{{cite journal | vauthors = Sharrocks AD | title = PIAS proteins and transcriptional regulation—more than just SUMO E3 ligases? | journal = Genes & Development | volume = 20 | issue = 7 | pages = 754–8 | date = April 2006 | pmid = 16600908 | doi = 10.1101/gad.1421006 | doi-access = free }}</ref> While PIAS proteins interact with at least 60 different proteins involved in transcription,<ref name="cytokines and PIAS Shuai" /> they are known to act as E3 SUMO-protein ligases.<ref name="SUMO Function"/> In essence, the RING-finger-like zinc-binding domain of the PIAS protein assists in the attachment of a SUMO protein to the target transcription factor. Attachment of a SUMO protein to the target allows for protein–protein interaction between PIAS and the transcription factor. This interaction can either upregulate or downregulate transcription.<ref name="SUMO interactions"/><ref name="sumoylation nature article">{{cite journal | vauthors = Geiss-Friedlander R, Melchior F | title = Concepts in sumoylation: a decade on | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 12 | pages = 947–56 | date = December 2007 | pmid = 18000527 | doi = 10.1038/nrm2293 | s2cid = 30462190 }}</ref> For example, the activity of transcription factor p73 was repressed after it was SUMOylated by PIAS1.<ref name="sumoylation of p73">{{cite journal | vauthors = Munarriz E, Barcaroli D, Stephanou A, Townsend PA, Maisse C, Terrinoni A, Neale MH, Martin SJ, Latchman DS, Knight RA, Melino G, De Laurenzi V | title = PIAS-1 is a checkpoint regulator which affects exit from G1 and G2 by sumoylation of p73 | journal = Molecular and Cellular Biology | volume = 24 | issue = 24 | pages = 10593–610 | date = December 2004 | pmid = 15572666 | pmc = 533962 | doi = 10.1128/MCB.24.24.10593-10610.2004 }}</ref> One function of PIAS proteins is to relocate transcriptional regulators to different compartments within the nucleus of the cell.<ref name="SUMO Function" />

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 | vauthors = Liu S, 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 | volume = 6 | issue = 4 | pages = 1045–1048 | date = October 2013 | pmid = 24137461 | pmc = 3796434 | doi = 10.3892/ol.2013.1472 }}</ref><ref name="PIAS1 and PIAS4 Function in DSB">{{cite journal | vauthors = Galanty Y, 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 | volume = 462 | issue = 7275 | pages = 935–9 | date = December 2009 | pmid = 20016603 | pmc = 2904806 | doi = 10.1038/nature08657 | bibcode = 2009Natur.462..935G }}</ref>

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.<ref name="IL-6 Principles">{{cite journal | vauthors = Heinrich PC, 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 | volume = 374 | issue = Pt 1 | pages = 1–20 | date = August 2003 | pmid = 12773095 | pmc = 1223585 | doi = 10.1042/BJ20030407 }}</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 STAT1 signaling.<ref name="STAT1 Inhibition"/><ref name="PIASy co-repressor">{{cite journal | vauthors = Liu B, 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 | volume = 98 | issue = 6 | pages = 3203–7 | date = March 2001 | pmid = 11248056 | pmc = 30631 | doi = 10.1073/pnas.051489598 | bibcode = 2001PNAS...98.3203L | doi-access = free }}</ref> PIAS3 was found to specifically inhibit STAT3 signaling after stimulation by the cytokine IL-6.<ref name="PIAS3 discovery" /> Also, it is known that PIAS1 can inhibit NF-κB activity upon stimulation by the cytokine TNF and the LPS endotoxin.<ref name="cytokines and PIAS Shuai" />

== Structure ==

thumb|350x450px|The domains (SAP, RLD, AD, S/T) and motifs (PINIT, SIM) found in most protein inhibitors of activated STAT (PIAS)

The three-dimensional protein structures of PIAS2,<ref name="PIAS2 3D structure">{{cite web|last=Dong|first=A.|title=Human protein inhibitor of activated STAT, 2 (E3 SUMO ligase)|url=http://www.thesgc.org/structures/4fo9|work=Structural Genomics Consortium (SGC)|access-date=5 May 2014}}</ref> PIAS3,<ref name="PIAS3 3D structure">{{cite web|last=Dong|first=A|title=Human protein inhibitor of activated STAT, 3|url=http://www.thesgc.org/structures/4mvt|work=Structural Genomics Consortium (SGC)|access-date=5 May 2014}}</ref> and PIAS-like protein SIZ1<ref name="Siz1 3D structure">{{cite journal | vauthors = Yunus AA, Lima CD | title = Structure of the Siz/PIAS SUMO E3 ligase Siz1 and determinants required for SUMO modification of PCNA | journal = Molecular Cell | volume = 35 | issue = 5 | pages = 669–82 | date = September 2009 | pmid = 19748360 | pmc = 2771690 | doi = 10.1016/j.molcel.2009.07.013 }}</ref> were recently solved using X-ray crystallography. The structures of PIAS2 and PIAS3 were listed in the Structural Genomics Consortium in 2012 and 2013, respectively, by A. Dong et al. Details of the SIZ1 structure were published by Ali A. Yunus and Christopher D. Lima in 2009.

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).<ref name="SUMO interactions" /><ref name="PIAS overview Shuai" /><ref name="cytokines and PIAS Shuai">{{cite journal | vauthors = Shuai K | title = Regulation of cytokine signaling pathways by PIAS proteins | journal = Cell Research | volume = 16 | issue = 2 | pages = 196–202 | date = February 2006 | pmid = 16474434 | doi = 10.1038/sj.cr.7310027 | s2cid = 755228 | doi-access = free }}</ref><ref name="finland structure">{{cite journal | vauthors = Palvimo JJ | title = PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription | journal = Biochemical Society Transactions | volume = 35 | issue = Pt 6 | pages = 1405–8 | date = December 2007 | pmid = 18031232 | doi = 10.1042/BST0351405 }}</ref>

{| class="wikitable sortable collapsible" |+ 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)<ref name="SUMO interactions" /><ref name="PIAS overview Shuai" /><ref name="cytokines and PIAS Shuai" /><ref name="SAP p53" /> |- | Pro-Ile-Asn-Ile-Thr motif || PINIT || nuclear retention<ref name="PINIT discovery" /> |- | RING-finger-like zinc-binding domain || RLD || SUMOylation; interaction with other proteins<ref name="SUMO interactions" /> |- | Highly acidic domain || AD || unknown<ref name="PIAS overview Shuai" /> |- | SUMO-interacting motif || SIM || recognition and interaction with SUMO proteins<ref name="SUMO interactions" /> |- | Serine/threonine-rich C-terminal region|| S/T || unknown<ref name="PIAS overview Shuai" /> |}

=== SAP ===

thumb|right|alt=p53 binding domain of PIAS-1|p53 binding domain of PIAS-1. The N-terminal scaffold attachment factor-A/B, acinus and PIAS (SAP) domain is found in all PIAS proteins.<ref name="cytokines and PIAS Shuai" /> It is composed of four alpha helices.<ref name="SAP p53">{{cite journal | vauthors = Okubo S, Hara F, Tsuchida Y, Shimotakahara S, Suzuki S, Hatanaka H, Yokoyama S, Tanaka H, Yasuda H, Shindo H | title = 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 = The Journal of Biological Chemistry | volume = 279 | issue = 30 | pages = 31455–61 | date = July 2004 | pmid = 15133049 | doi = 10.1074/jbc.M403561200 | s2cid = 9187033 | doi-access = free }}</ref> 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.<ref name="SAP">{{cite journal | vauthors = Aravind L, Koonin EV | title = SAP – a putative DNA-binding motif involved in chromosomal organization | journal = Trends in Biochemical Sciences | volume = 25 | issue = 3 | pages = 112–4 | date = March 2000 | pmid = 10694879 | doi = 10.1016/s0968-0004(99)01537-6 }}</ref> 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.<ref name="PIAS overview Shuai" /><ref name="cytokines and PIAS Shuai" /> SAP also binds to p53.<ref name="SAP p53" />

Each SAP domain contains an LXXLL amino acid motif.<ref name="cytokines and PIAS Shuai" /> 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.<ref name="nuclear receptors">{{cite journal | vauthors = Glass CK, Rosenfeld MG | title = The coregulator exchange in transcriptional functions of nuclear receptors | journal = Genes & Development | volume = 14 | issue = 2 | pages = 121–41 | date = January 2000 | pmid = 10652267 | doi = 10.1101/gad.14.2.121 | s2cid = 12793980 | doi-access = free }}</ref>

=== PINIT ===

The Pro-Ile-Asn-Ile-Thr (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.<ref name="PINIT discovery">{{cite journal | vauthors = Duval D, Duval G, Kedinger C, Poch O, Boeuf H | title = The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L | journal = FEBS Letters | volume = 554 | issue = 1–2 | pages = 111–8 | date = November 2003 | pmid = 14596924 | doi = 10.1016/s0014-5793(03)01116-5 | s2cid = 23261716 | doi-access = free | bibcode = 2003FEBSL.554..111D }}</ref>

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.<ref name="PINIT not in PIAS4E6-"/>

=== 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<ref name="SUMO interactions" />

=== AD and SIM ===

The highly acidic domain (AD), present in all PIAS proteins, contains a SUMO-interacting motif (SIM).<ref name="cytokines and PIAS Shuai" /> 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.<ref name="SUMO interactions" /> The function of the highly acidic domain is unknown.<ref name="PIAS overview Shuai" />

=== S/T ===

The Serine/threonine-rich C-terminal (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.<ref name="cytokines and PIAS Shuai" /> Furthermore, the length of this region varies among PIAS protein isoforms.<ref name="SUMO interactions" /> The function of the S/T region is unknown.<ref name="PIAS overview Shuai" />

{| class="wikitable sortable collapsible" |+ Structural differences between PIAS proteins |- ! Type<ref name="SUMO interactions" /><ref name="PIAS overview Shuai" /> !! Amino acid length<ref name="SUMO interactions" /> !! Protein regions<ref name="SUMO interactions" /><ref name="PIAS overview Shuai" /> |- | 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 |}

== Potential applications ==

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 increased resistance of HeLa cells to ionizing radiation.<ref name="PIAS 3 Function" /> This indicates a significant role for PIAS3 in DNA repair.<ref name="PIAS 3 Function" /> Additionally, overexpression of PIAS3 inhibited human lung cancer cell growth in vitro and rendered cancer cells up to twelve times more sensitive to chemotherapeutic drugs.<ref name="PIAS lung cancer">{{cite journal | vauthors = Ogata Y, Osaki T, Naka T, Iwahori K, Furukawa M, Nagatomo I, Kijima T, Kumagai T, Yoshida M, Tachibana I, Kawase I | title = Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation | journal = Neoplasia | volume = 8 | issue = 10 | pages = 817–25 | date = October 2006 | pmid = 17032498 | pmc = 1715929 | doi = 10.1593/neo.06409 }}</ref> 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.<ref name="PIAS in GBM">{{cite journal | vauthors = Brantley EC, Nabors LB, Gillespie GY, Choi YH, Palmer CA, Harrison K, Roarty K, Benveniste EN | title = Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression | journal = Clinical Cancer Research | volume = 14 | issue = 15 | pages = 4694–704 | date = August 2008 | pmid = 18676737 | pmc = 3886729 | doi = 10.1158/1078-0432.CCR-08-0618 }}</ref> 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.<ref name="mRNA of BRCA, PIAS1, and PIAS4 in gastric cancer">{{cite journal | vauthors = Wei J, Costa C, Ding Y, Zou Z, Yu L, Sanchez JJ, Qian X, Chen H, Gimenez-Capitan A, Meng F, Moran T, Benlloch S, Taron M, Rosell R, Liu B | title = mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer | journal = Journal of the National Cancer Institute | volume = 103 | issue = 20 | pages = 1552–6 | date = October 2011 | pmid = 21862729 | doi = 10.1093/jnci/djr326 | doi-access = }}</ref>

Continuous activation of the JAK-STAT pathway can cause cancer in humans as well as less complex organisms such as Drosophila.<ref>{{cite journal | vauthors = Amoyel M, Anderson AM, Bach EA | title = JAK/STAT pathway dysregulation in tumors: a Drosophila perspective | journal = Seminars in Cell & Developmental Biology | volume = 28 | pages = 96–103 | date = April 2014 | pmid = 24685611 | doi = 10.1016/j.semcdb.2014.03.023 | pmc = 4037387 }}</ref> Given the preliminary evidence and their effects on important signaling pathways involved in cancer, 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.<ref name="PIAS 3 Function" /><ref name="PIAS lung cancer" />

In addition to its importance in various cancers, the JAK-STAT signaling pathway plays an important part in the human immune response and in particular with regards to adaptive immunity.<ref name="Evolution of JAK-STAT Pathway & Immune System">{{cite journal | vauthors = Liongue C, O'Sullivan LA, Trengove MC, Ward AC | title = Evolution of JAK-STAT pathway components: mechanisms and role in immune system development | journal = PLOS ONE | volume = 7 | issue = 3 | article-number = e32777 | year = 2012 | pmid = 22412924 | pmc = 3296744 | doi = 10.1371/journal.pone.0032777 | bibcode = 2012PLoSO...732777L | doi-access = free }}</ref> Clinical proof of concept for the use of JAK inhibitors for treatment of autoimmune and inflammatory disease has been demonstrated by Pfizer's tofacitinib, a JAK inhibitor recently approved in the US for the treatment of rheumatoid arthritis.<ref>{{cite web|title=FDA Press Release Regarding Approval of Tofacitinib|website=Food and Drug Administration|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm|archive-url=https://web.archive.org/web/20121109060048/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm|archive-date=9 November 2012|access-date=6 May 2014}}</ref> Additionally, tofacitinib is currently being studied for the treatment of ankylosing spondylitis, psoriatic arthritis, psoriasis, atopic dermatitis, and inflammatory bowel disease.<ref name="Pfizer website">{{cite web|title=Pfizer's Product Pipeline|url=http://www.pfizer.com/research/science_and_technology/product_pipeline|access-date=6 May 2014}}</ref>

Furthermore, STAT1 and STAT2 are essential factors in the cellular antiviral and adaptive immune defenses.<ref name="STAT1 and STAT2 Review">{{cite journal | vauthors = Au-Yeung N, Mandhana R, Horvath CM | title = Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway | journal = JAK-STAT | volume = 2 | issue = 3 | article-number = e23931 | date = July 2013 | pmid = 24069549 | pmc = 3772101 | doi = 10.4161/jkst.23931 }}</ref> PIAS proteins and other regulators are necessary for homeostasis and for fine tuning the immune response.<ref>{{cite journal | vauthors = Morales JK, Falanga YT, Depcrynski A, Fernando J, Ryan JJ | title = Mast cell homeostasis and the JAK-STAT pathway | journal = Genes and Immunity | volume = 11 | issue = 8 | pages = 599–608 | date = December 2010 | pmid = 20535135 | pmc = 3099592 | doi = 10.1038/gene.2010.35 }}</ref> PIAS proteins regulate STAT transcription through several mechanisms, and genetic studies in rodents have shown that PIAS1 plays an important physiological role in STAT1 regulation. Many of the 60 proteins that PIAS protein family is believed to interact with are immune regulatory factors.<ref name="cytokines and PIAS Shuai" />

== References == {{reflist|33em}}

== External links == * [http://pir.georgetown.edu/cgi-bin/ipcSF?id=PIRSF038860 PIAS protein entry] at the Protein Information Resource (PIR) * {{MeshName|PIAS+Proteins}}

{{JAK-STAT signaling pathway}}

Category:Proteins Category:Cell signaling