Topors acts as a SUMO‐1 E3 ligase for p53 in vitro and in vivo

Weger, Stefan; Hammer, Eva; Heilbronn, Regine

doi:10.1016/j.febslet.2005.07.088

Cited by 159 publications

(128 citation statements)

References 26 publications

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“…Precedent for such a dual-activity protein is provided by the conserved RING-finger protein, Topors. Topors binds DNA topoisomerase I [50] and p53 [51,52] and it displays both Ub E3 ligase [53,54] and SUMO ligase activity [55]. Topors Ub ligase activity is dependent on its RING-finger domain, while its SUMO ligase activity is not [55].…”

Section: Discussionmentioning

confidence: 99%

Stimulation of in vitro sumoylation by Slx5–Slx8: Evidence for a functional interaction with the SUMO pathway

et al. 2007

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The yeast genes SLX5 and SLX8 were identified based on their requirement for viability in the absence of the Sgs1 DNA helicase. Loss of these genes results in genome instability, nibbled colonies, and other phenotypes associated with defects in sumoylation. The Slx5 and Slx8 proteins form a stable complex and each subunit contains a single RING-finger domain at its C-terminus. To determine the physiological function of the Slx5-8 complex, we explored its interaction with the SUMO pathway. Curing 2μ circle from the mutants suppressed their nibbled colony phenotype and partially improved their growth rate, but did not affect their sensitivity to hydroxyurea. The increase in sumoylation observed in slx5Δ and slx8Δ mutants was found to be dependent on the Siz1 SUMO ligase. Physical interactions between the Slx5-8 complex and both Ubc9 and Smt3 were identified and characterized. Using in vitro reactions, we show that Slx5, Slx8, or the Slx5-8 complex stimulates the formation of SUMO chains and the sumoylation of a test substrate. Interestingly, a functional RING-finger domain is not required for this stimulation in vitro. These biochemical data demonstrate for the first time that the Slx5-8 complex is capable of interacting directly with the SUMO pathway.

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Section: Discussionmentioning

confidence: 99%

Stimulation of in vitro sumoylation by Slx5–Slx8: Evidence for a functional interaction with the SUMO pathway

et al. 2007

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“…Several studies showed that wild type p53 protein is modified by SUMO. Topors SUMO-1 E3 ligase enhances the conjugation of SUMO-1 to p53 at lysine 386 in vivo (60). SUMO ligases PIAS1 and PIASx␤ together with Ubc9-conjugating enzyme modify p53 at lysine 386 and repress the transcriptional activity of p53 (61).…”

Section: Discussionmentioning

confidence: 99%

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

Yan¹,

Zhang²,

Zhang

et al. 2011

Journal of Biological Chemistry

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p53 is frequently mutated in tumor cells, and mutant p53 is often highly expressed due to its increased half-life. Thus, targeting mutant p53 for degradation might be explored as a therapeutic strategy to manage tumors that are addicted to mutant p53 for survival. Arsenic trioxide, a drug for patients with acute promyelocytic leukemia, is found to target and degrade a class of proteins with high levels of cysteine residues and vicinal thiol groups, such as promyelocytic leukemia protein (PML) and PML-retinoic acid receptor ␣ fusion protein. Interestingly, wild type p53 is accumulated in cells treated with arsenic compounds, presumably due to arsenic-induced oxidative stresses. In this study, we found that wild type p53 is induced by arsenic trioxide in tumor cells, consistent with published studies. In contrast, we found that arsenic compounds degrade both endogenous and ectopically expressed mutant p53 in time-and dose-dependent manners. We also found that arsenic trioxide decreases the stability of mutant p53 protein through a proteasomal pathway, and blockage of mutant p53 nuclear export can alleviate the arsenic-induced mutant p53 degradation. Furthermore, we found that knockdown of endogenous mutant p53 sensitizes, whereas ectopic expression of mutant p53 desensitizes, tumor cells to arsenic treatment. Taken together, we found that mutant p53 is a target of arsenic compounds, which provides an insight into exploring arsenic compound-based therapy for tumors harboring a mutant p53.

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“…In vitro sumoylation reactions were also performed with p53 as a substrate (40,41). Limiting amounts of Ubc9 were used and SUMO3 conjugation to p53 was hardly detectable at early timepoints.…”

Section: Sf2/asf Interacts With Ubc9 and Stimulates Sumoylation Of Spmentioning

confidence: 99%

The serine/arginine-rich protein SF2/ASF regulates protein sumoylation

Pelisch

Gerez

Druker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Protein modification by conjugation of small ubiquitin-related modifier (SUMO) is involved in diverse biological functions, such as transcription regulation, subcellular partitioning, stress response, DNA damage repair, and chromatin remodeling. Here, we show that the serine/arginine-rich protein SF2/ASF, a factor involved in splicing regulation and other RNA metabolism-related processes, is a regulator of the sumoylation pathway. The overexpression of this protein stimulates, but its knockdown inhibits SUMO conjugation. SF2/ASF interacts with Ubc9 and enhances sumoylation of specific substrates, sharing characteristics with already described SUMO E3 ligases. In addition, SF2/ASF interacts with the SUMO E3 ligase PIAS1 (protein inhibitor of activated STAT-1), regulating PIAS1-induced overall protein sumoylation. The RNA recognition motif 2 of SF2/ASF is necessary and sufficient for sumoylation enhancement. Moreover, SF2/ASF has a role in heat shock-induced sumoylation and promotes SUMO conjugation to RNA processing factors. These results add a component to the sumoylation pathway and a previously unexplored role for the multifunctional SR protein SF2/ASF. posttranslational modification | splicing factor | RNA processing | E3 ligase S er/Arg-rich (SR) proteins were first described as regulators of both constitutive and alternative splicing (1, 2). They are characterized by a modular structure consisting of a C terminal domain-rich in arginine and serine dipeptides (RS domain) and one or two N-terminal RNA-recognition motifs (RRMs) (1). Although RS domains were first identified as protein-protein interaction platforms, it has been shown that they contact the RNA directly at the splicing branch point and the 5′ splice site (3, 4). In addition, RRMs, originally reported to contact the RNA, were shown to mediate protein-protein interactions (5). The function of SR proteins exceeds splicing regulation (2, 6). They regulate transcription (7), mRNA export (8), mRNA stability (9, 10), translation (5, 11), and genome stability (12, 13). Splicing factor 2/alternative splicing factor [SF2/ASF, recently renamed SRSF1 (14)] is a prototypical member of the SR protein family (15, 16). Its second RRM (RRM2) is required for translation regulation via mammalian target of rapamycin binding (5) and for SF2/ASF recruitment to nuclear stress bodies (nSBs) upon heat shock (17, 18).Small ubiquitin-related modifier (SUMO) is a transient and reversible posttranslational protein modifier (19)(20)(21). SUMO proteins (SUMO1 to -4) are expressed in an immature proform that carries a C-terminal stretch of variable length. Removal of this C-terminal extension by SUMO-specific proteases (SENPs) leaves an invariant Gly-Gly motif that marks the C terminus of the mature protein (22). The steps involved in the SUMO pathway resemble those of the ubiquitin pathway (23). The first step is the ATP-dependent activation of a mature SUMO protein by the SUMO-specific E1 activating enzyme heterodimer (SAE I/SAE II in mammals). Next, SUMO is transferred from ...

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Topors acts as a SUMO‐1 E3 ligase for p53 in vitro and in vivo

Cited by 159 publications

References 26 publications

Stimulation of in vitro sumoylation by Slx5–Slx8: Evidence for a functional interaction with the SUMO pathway

Stimulation of in vitro sumoylation by Slx5–Slx8: Evidence for a functional interaction with the SUMO pathway

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

The serine/arginine-rich protein SF2/ASF regulates protein sumoylation

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