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

Mary L. Spengler, Li Wu Guo, Michael G Brattain

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 NF?B2-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.

Original languageEnglish (US)
Pages (from-to)623-630
Number of pages8
JournalCell Cycle
Volume7
Issue number5
DOIs
StatePublished - Mar 1 2008

Fingerprint

Phosphorylation
Serine
Lysine
Degradation
Processing
Cell Cycle
Up-Regulation
Sumoylation
Cells
Cell signaling
Colforsin
Ubiquitin
Isoenzymes
Cell growth
Transcription
Carcinogenesis
Phosphotransferases
Amino Acids
Genes
Growth

Keywords

  • Degradation
  • Key regulatory lysine
  • Phosphorylation
  • Proteolytic processing
  • Sp1
  • Sumoylation
  • Transcriptional regulation
  • Ubiquitinylation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation. / Spengler, Mary L.; Guo, Li Wu; Brattain, Michael G.

In: Cell Cycle, Vol. 7, No. 5, 01.03.2008, p. 623-630.

Research output: Contribution to journalArticle

Spengler, Mary L. ; Guo, Li Wu ; Brattain, Michael G. / Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation. In: Cell Cycle. 2008 ; Vol. 7, No. 5. pp. 623-630.
@article{4d65998f95764e9fafd4372cde5348f1,
title = "Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation",
abstract = "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 NF?B2-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.",
keywords = "Degradation, Key regulatory lysine, Phosphorylation, Proteolytic processing, Sp1, Sumoylation, Transcriptional regulation, Ubiquitinylation",
author = "Spengler, {Mary L.} and Guo, {Li Wu} and Brattain, {Michael G}",
year = "2008",
month = "3",
day = "1",
doi = "10.4161/cc.7.5.5402",
language = "English (US)",
volume = "7",
pages = "623--630",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "5",

}

TY - JOUR

T1 - Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation

AU - Spengler, Mary L.

AU - Guo, Li Wu

AU - Brattain, Michael G

PY - 2008/3/1

Y1 - 2008/3/1

N2 - 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 NF?B2-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.

AB - 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 NF?B2-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.

KW - Degradation

KW - Key regulatory lysine

KW - Phosphorylation

KW - Proteolytic processing

KW - Sp1

KW - Sumoylation

KW - Transcriptional regulation

KW - Ubiquitinylation

UR - http://www.scopus.com/inward/record.url?scp=41849083427&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41849083427&partnerID=8YFLogxK

U2 - 10.4161/cc.7.5.5402

DO - 10.4161/cc.7.5.5402

M3 - Article

VL - 7

SP - 623

EP - 630

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 5

ER -