![]() PIAS1 overexpression has a significant influence on cell proliferation, cell migration, and motility. ![]() In this study, we first evaluate the effects of PIAS1 overexpression in HeLa cells. ![]() Altogether, these reports suggest that PIAS1 could promote cancer cell growth and progression by regulating the SUMOylation level on a pool of different substrates. SUMOylation of MYC leads to a longer half-life and therefore an increase in oncogenic activity 23. In B-cell lymphoma, PIAS1 has been reported as a mediator in lymphomagenesis through SUMOylation of MYC, a proto-oncogene transcription factor associated with several cancers. This is accomplished by ATO promoting the hyperSUMOylation of PML-RARα in a PIAS1-dependent manner, resulting in the ubiquitin-dependent proteasomal degradation of PML-RARα and APL remission 26. In addition to its regulatory role in PML/PML-RARα oncogenic signaling, PIAS1 has been shown to be involved in the cancer therapeutic mechanism of arsenic trioxide (ATO). PIAS1 can also regulate oncogenic signaling through the SUMOylation of promyelocytic leukemia (PML) and its fusion product with the retinoic acid receptor-α (PML-RARα) as observed in acute PML (APL) 26. In yeast, Lys-164 SUMOylation on proliferating cell nuclear antigen (PCNA) is strictly dependent on the PIAS1 ortholog Siz1 and is recruited to the anti-recombinogenic helicase Srs2 during S-phase 25. PIAS1 can SUMOylate the focal adhesion kinase (FAK) at Lys-152, a modification that dramatically increases its ability to autophosphorylate Thr-397, activate FAK, and promote the recruitment of several enzymes including Src family kinases 24. PIAS1 overexpression was reported in several cancers, including prostate cancer, multiple myeloma, and B-cell lymphomas 20– 23. Previous studies indicated that PIAS1 interacts with activated STAT1 and suppresses its binding to DNA 8. PIAS1 is one of the most well-studied E3 SUMO ligases and was initially reported as the inhibitor of signal transducers and activators of transcription 1 (STAT1) 19. Although several functions have been attributed to these domains, relatively little is known about the role of the poorly conserved C-terminus serine/threonine-rich region. The PIAS SIM (SUMO interaction motif) recognizes SUMO moieties of modified substrates and alters subnuclear targeting and/or assembly of transcription complex 16– 18. The Siz/PIAS RING (SP-RING) domain interacts with UBC9 and facilitates the transfer of SUMO to the substrate 16. The PINIT motif affects subcellular localization and contributes to substrate selectivity 14, 15. An example of this is the SAF-A/B, Acinus and PIAS (SAP) domain, which has a strong affinity towards A–T-rich DNA 11 and binds to Matrix attachment regions DNA 12, in addition to having an important role in substrate recognition 13. Overall, five different domains or motifs on PIAS family proteins recognize distinct sequences or conformations on target proteins, unique DNA structures, or specific “bridging” molecules to mediate their various functions 10. PIAS orthologs can be found through eukaryote cells and comprise four PIAS proteins (PIAS1, PIASx (PIAS2), PIAS3, and PIASy (PIAS4)), which share a high degree of sequence homology 9. ![]() To date, several structurally unrelated classes of proteins appear to act as E3 SUMO ligases in mammalian cells, such as the protein inhibitor of activated STAT (PIAS) family of proteins, Ran-binding protein 2, the polycomb group protein (Pc2), and topoisomerase I- and p53-binding protein (TOPORS) 7, 8. It is believed that SUMOylation events occurring without the aid of E3 SUMO ligases arise primarily on the consensus motif composed of ψK圎, where ψ represents a large hydrophobic residue and x represents any amino acid 6. Unlike ubiquitination, in vitro SUMOylation can occur without E3 SUMO ligases, although enhanced substrate specificity is conferred by E3 SUMO ligases 5. The conjugation of SUMO to target proteins requires an E1-activating enzyme (SAE1/2), an E2-conjugating enzyme (UBC9), and one of several E3 SUMO ligases 4. These proteases also cleave the isopeptide bond formed between the ε-amino group of the acceptor lysine residues and the C-terminus residue of the conjugated SUMO proteins. Prior to conjugation, the immature SUMO proteins are C-terminally processed by sentrin-specific proteases 3. SUMO proteins are highly conserved through evolution and the human genome encodes four SUMO genes, of which three genes ( SUMO1, SUMO2, and SUMO3) are ubiquitously expressed in all cells 1, 2. The small ubiquitin-like modifier (SUMO) protein is an ubiquitin-like (UBL) protein that is highly dynamic and can reversibly target lysine residues on a wide range of proteins involved in several essential cellular events, including protein translocation and degradation, mitotic chromosome segregation, DNA damage response, cell cycle progression, cell differentiation, and apoptosis 1.
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