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==Functions==
==Functions==
PIAS proteins contribute to the control of gene expression, and may be considered [[Transcription coregulator|transcriptional co-regulators]].<ref name="SUMO Function">{{cite journal|last=Sharrocks|first=A. D.|title=PIAS proteins and transcriptional regulation--more than just SUMO E3 ligases?|journal=Genes & Development|date=17 March 2006|volume=20|issue=7|pages=754–758|doi=10.1101/gad.1421006}}</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 small [[ubiquitin]]-related modifiers ([[SUMO protein|SUMOs]]).<ref name="SUMO Function"/> PIAS proteins can be either activators or repressors, depending on the target gene or transcriptional co-regulator<ref name="SUMO Function" /> . One mechanism through which PIAS proteins operate appear to be through relocalization of transcriptional regulators to different subnucelar compartments<ref name="SUMO Function" /> .
PIAS proteins contribute to the control of gene expression, and may be considered [[Transcription coregulator|transcriptional co-regulators]].<ref name="SUMO Function">{{cite journal|last=Sharrocks|first=A. D.|title=PIAS proteins and transcriptional regulation--more than just SUMO E3 ligases?|journal=Genes & Development|date=17 March 2006|volume=20|issue=7|pages=754–758|doi=10.1101/gad.1421006}}</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 small [[ubiquitin]]-related modifiers ([[SUMO protein|SUMOs]]).<ref name="SUMO Function"/>. Depending on the target gene or transcriptional co-regulator, PIAS proteins can be activators or repressors <ref name="SUMO Function" /> . 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 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=2013 Oct|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=2009 Dec 17|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=2013 Oct|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=2009 Dec 17|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">{{cite journal|last=Liu|first=B|coauthors=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|date=1998 Sep 1|volume=95|issue=18|pages=10626-31|pmid=9724754}}</ref><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=2001 Mar 13|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]]. Although the exact mechanism isn’t clear, PIAS1 and PIASy both inhibit STAT-1 signaling.<ref name="STAT1 Inhibition">{{cite journal|last=Liu|first=B|coauthors=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|date=1998 Sep 1|volume=95|issue=18|pages=10626-31|pmid=9724754}}</ref><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=2001 Mar 13|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" />

Revision as of 03:02, 16 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, such as sumoylation. More specifically, they can act as E3 SUMO-protein ligases.

Four proteins are known to belong to the mammalian PIAS family: PIAS1, PIAS2 (also known as PIASx), PIAS3, and PIAS4 (also known as PIASy). Apart from PIAS1, each PIAS protein has two isoforms. Homologues of PIAS proteins have been found in other eukaryotes, including Zimp/dPIAS in Drosophila melanogaster and zfPIAS4a in zebrafish. Two PIAS-like proteins, SIZ1 and SIZ2, were identified in yeast.

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

Discovery

While studying the JAK-STAT pathway, PIAS3 was discovered. It was the first discovery made of the PIAS protein family.[1] Identification of the other members soon followed. The interaction between STATs and PIASs was characterized by the yeast two-hybrid assay.[1] 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]

Structure

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

The sizes of PIAS proteins differ. PIAS4 is the smallest with an estimated 510 amino acid residues. PIAS1 is the largest with 650 amino acid residues. PIAS2 and PIAS3 fall within these ranges. [3] 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 really interesting new gene (RING) domain, the highly acidic region (AD), the SUMO-interacting motif (SIM), and the serine/threonine-rich C-terminal region (S/T).[4][3][5][6]

SAP domain

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

The SAP domain is found in all PIAS proteins.[6] It is composed of four alpha helices.[7] 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.[8] 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.[4][6] SAP also binds to p53.[7]

Each SAP domain contains an LXXLL amino acid motif.[6] 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.[9]

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 PIAS proteins, such as PIAS3 and PIAS3L, to the nucleus.[10]

The PINIT motif is not found in PIAS4 isoform PIAS4E6-.[11]

RING domain

The RING domain is essential for PIAS proteins to function as E3 SUMO-protein ligases. This domain is present in all PIAS proteins. [3]

AD and SIM

The AD domain, present in all PIAS proteins, contains a SIM motif.[6] The SIM motif may be needed for PIAS proteins to accurately recognize other SUMO proteins. However, it is not needed for E3 SUMO-protein ligase activity to occur.[3]

S/T region

The S/T region is not found in all PIAS proteins. PIAS4 is the only member of the PIAS protein family that lacks this region. [6] Furthermore, the length of this region varies among PIAS protein isoforms.[3]

Functions

PIAS proteins contribute to the control of gene expression, and may be considered transcriptional co-regulators.[12] While PIAS proteins interact with at least 60 different proteins involved in transcription,[6] they are known to act as small ubiquitin-related modifiers (SUMOs).[12]. Depending on the target gene or transcriptional co-regulator, PIAS proteins can be activators or repressors [12] . One function of PIAS proteins is to relocate transcriptional regulators to different compartments within the nucleus of the cell [12] .

PIAS proteins also play a key role in double-stranded break DNA repair.[13] 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.[13] PIAS1, PIAS3, and PIAS4 have been shown to recruit proteins to the site of the damage and promote repair.[13][14]

Additionally, PIAS proteins are important transcriptional co-regulators of the JAK/STAT signaling pathway. Although the exact mechanism isn’t clear, PIAS1 and PIASy both inhibit STAT-1 signaling.[15][16] 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.[13] This indicates a significant role for PIAS3 in DNA repair.[13] Additionally, overexpression of PIAS3 inhibited human lung cancer cell growth in vitro and rendered cancer cells up to 12X more sensitive to chemotherapeutic drugs.[17] 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.[18] Inhibition of PIAS3 resulted in increased glioblastoma propagation, while PIAS3 overexpression inhibited STAT-3 signaling and cell proliferation . Furthermore, in a retrospective study of advanced gastric cancer patients who had received second-line docetaxel-based chemotherapy, patients who had high or intermediate levels of BRCA1, PIAS1, and PIAS4 showed longer survival.[19]

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.[13][17]

See also

References

  1. ^ a b c d Chung, CD (1997 Dec 5). "Specific inhibition of Stat3 signal transduction by PIAS3". Science (New York, N.Y.). 278 (5344): 1803–5. PMID 9388184. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ Liu, B (1998 Sep 1). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ a b c d e f 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 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)
  5. ^ 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.
  6. ^ a b c d e f g Shuai, Ke (February 2006). "Regulation of cytokine signaling pathways by PIAS proteins". Cell Research. 16 (2): 196–202. doi:10.1038/sj.cr.7310027.
  7. ^ a b 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)
  8. ^ Aravind, L (2000 Mar). "SAP - a putative DNA-binding motif involved in chromosomal organization". Trends in biochemical sciences. 25 (3): 112–4. PMID 10694879. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Glass, CK (2000 Jan 15). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes & development. 14 (2): 121–41. PMID 10652267. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ Duval, D (2003 Nov 6). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Wong, KA (2004 Jun). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ 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.
  13. ^ a b c d e f Liu, S (2013 Oct). "PIAS3 promotes homology-directed repair and distal non-homologous end joining". Oncology letters. 6 (4): 1045–1048. PMID 24137461. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ Galanty, Y (2009 Dec 17). "Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks". Nature. 462 (7275): 935–9. PMID 20016603. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  15. ^ Liu, B (1998 Sep 1). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Liu, B (2001 Mar 13). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ a b Ogata, Y (2006 Oct). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  18. ^ Brantley, EC (2008 Aug 1). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  19. ^ Wei, J (2011 Oct 19). "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}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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