Sumoylation of internally initiated Sp3 isoforms regulates transcriptional repression via a Trichostatin A-insensitive mechanism

Spengler, Mary L.; Kennett, Sarah B.; Moorefield, K. Scott; Simmons, Steven O.; Brattain, Michael G.; Horowitz, Jordan M.

doi:10.1016/j.cellsig.2004.06.007

Cited by 29 publications

(37 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, for Sp3, we have observed striking differences of protein half life depending on the presence of growth factors. Our data further increase the complexity of the regulation of Sp3 in particular the fact that different Sp3 isoforms result for internal initiation of translation (Kennett et al, 1997) but also the recent advances showing that sumoylation of Sp3 represses its transcriptional activity (Sapetschnig et al, 2002(Sapetschnig et al, , 2004Spengler et al, 2005). It is interesting to note that the Erk phosphorylation site is situated in the long Sp3 isoform, which behaves as an activator of transcription (Kennett et al, 1997) or a repressor depending on the promoter (Lambiase et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Sp3‐Mediated VEGF regulation is dependent on phosphorylation by extra‐cellular signals regulated kinases (Erk)

Pagès

2007

Journal Cellular Physiology

View full text Add to dashboard Cite

We have previously demonstrated that phosphorylation by Erk of Sp1 was essential for its full activity in the context of the VEGF promoter. Here, we show that Sp3, which, as Sp1, belongs to the GC-rich binding transcription factor family, is also phosphorylated by Erk in vitro on serine 73. We have established cell lines in which expression of wild-type Sp3 or a serine 73 to alanine (S73A) mutant is controlled by tetracycline. One of these cells lines also express the Raf:ER chimera which permits stimulation of Erk by tamoxifen. Difference in electrophoretic mobility and antibody directed against the phosphorylated serine 73 demonstrate that it is phosphorylated in vivo. Wild-type Sp3 half-life is increased upon Erk activation but the S73 is poorly implicated in this mechanism suggesting that Erkdependent Sp3 stability depends on other(s) domain(s) of the protein. Electro-mobility shift assays and utilization of Gal4/Sp3 chimeric proteins show that Erk does not alter Sp3 DNA binding capacity but enhances its transcriptional activity. The S73A mutant Sp3 posses a reduced activity in Erk-stimulated cells. In the inducible cell lines, expression of wild-type form of Sp3 increases VEGF production whereas the S73A form has a reduced potential reflecting its lower transcriptional activity. Altogether our results described a new link between constitutive Erk activity and the regulation of VEGF expression two common denominators implicated in tumor angiogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Sp3‐Mediated VEGF regulation is dependent on phosphorylation by extra‐cellular signals regulated kinases (Erk)

Pagès

2007

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…SUMO-dependent transcriptional repression appears to be independent of HDACs (64). Horowitz and colleagues found that Sp3 isoforms (Sp3, M1, and M2) are sumoylated at Lys551 (60). Recent studies indicate that levels of sumoylated Sp1 are attenuated during tumorigenesis (66).…”

Section: Chromatin Recruitment and Dna Damagementioning

confidence: 99%

“…Sumoylated Sp1 is found in the cytosol interacting with rpt6, and this interaction leads to increased Sp1 proteolysis and degradation (66). Decreased levels of cytosolic Sp1 as a consequence of sumoylation reduce the pool of Sp1 that would otherwise migrate to the nucleus (60). Modifications of Sp1 can occur simultaneously and synergistically.…”

Section: Chromatin Recruitment and Dna Damagementioning

confidence: 99%

Sp1 Phosphorylation and Its Regulation of Gene Transcription

Tan

Khachigian

2009

Molecular and Cellular Biology

295

255

View full text Add to dashboard Cite

“…33,34 Therefore Lysine-551 may act as a molecular switch controlling the SUMO-mediated repression and acetyl-mediated activation of Sp3. Similarly, Sp1 KRL-16 serves as a molecular switch that is controlled by the competing homologous modifiers SUMO-1 (repression) and ubiquitin (activation/proteolytic processing).…”

confidence: 99%

Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation

Spengler

Guo²,

Brattain³

2008

Cell Cycle

Self Cite

View full text Add to dashboard Cite

Cell signaling pathways induce Sp1 phosphorylation, which allows for the upregulation of Sp1-dependent genes that control cell growth, cell cycle progression, survival and tumorigenesis. Sp1 activity is under constitutive repression through the sumoylation of Lysine-16, and Lysine-16 dependent N-terminal cleavage relieves this repression. The present investigation probes further into the mechanisms of Sp1 processing, desumoylation and degradation to reveal that phosphorylation is the major driving force behind these coupled activities. The first 7 amino acid residues of Sp1 enhance the accessibility of Lysine-16 to the homologous modifiers SUMO-1 and ubiquitin; and Serine-7 specifically enhances ubiquitinylation. Our data show that Serine-59 regulates Sp1 proteolytic processing, and thereby provides a mechanism for the upregulation of Sp1-dependent transcription by CyclinA/cdk2 phosphorylation of Serine-59. Sp1 activators, forskolin and PMA, enhance Sp1 processing in MCFE cells through distinct signaling pathways. PKC, ERK and ERBB2 kinase inhibitors suppress PMA induction of Sp1 and the specific isozyme PKCα enhances Sp1 cleavage. Sp1 contains several NFκB2-like proteolytic processing components including a functional phosphorylation-dependent β-TrCP binding motif. From these data, we propose a model by which cell cycle and mitotic kinases induce Sp1 proteolytic processing resulting in a desumoylated, derepressed and unstable Sp1 product.

show abstract

Sumoylation of internally initiated Sp3 isoforms regulates transcriptional repression via a Trichostatin A-insensitive mechanism

Cited by 29 publications

References 53 publications

Sp3‐Mediated VEGF regulation is dependent on phosphorylation by extra‐cellular signals regulated kinases (Erk)

Sp3‐Mediated VEGF regulation is dependent on phosphorylation by extra‐cellular signals regulated kinases (Erk)

Sp1 Phosphorylation and Its Regulation of Gene Transcription

Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation

Contact Info

Product

Resources

About