A role for a p21-E2F interaction during senescence arrest of normal human fibroblasts

Cynthia A. Afshari, Michael A. Nichols, Yue Xiong, Maria Mudryj

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The family of E2F transcription factors forms different multiprotein complexes with cell cycle regulatory proteins to control the expression of genes important in cell proliferation. In this study, we identified four distinct E2F complexes present in aged and senescent normal, human diploid fibroblasts. Two appeared to be identical to the previously described G1- specific p130 and Rb-E2F complexes present in young G0-arrested cells. The other two were novel E2F complexes that contained the cyclin-dependent kinase inhibitor p21 (cip1/WAF1/Sdi1/CAP20/PIC1) complexed with Rb/CDK2/cyclin E or with the Rb-related p107/CDK2/cyclin D. These p21-E2F complexes, while present in young G1 cells at very low levels, were elevated in senescent cells. The p21 containing E2F complexes were not detected during the S-phase in young cells. The DNA-binding stability of the p21 complexes was approximately 10 times greater than the stability of any other E2F complex or uncomplexed E2F. Addition of purified p21 protein to the S-phase-specific cyclin A/CDK2-p107-E2F complex from young cells dissociated cyclin A and CDK2 from p107/E2F, suggesting an additional novel function for p21. Finally, expression of p21 specifically inhibited transcription from an E2F-dependent promoter but had no effect on a mutant E2 promoter. In addition to its inhibition of CDK enzymes and proliferating cell nuclear antigen function in DNA replication, these studies reveal a novel mechanism by which p21 mediates growth arrest: direct interaction with E2F complexes and negative regulation of E2F transcription factor activity.

Original languageEnglish (US)
Pages (from-to)979-988
Number of pages10
JournalCell Growth and Differentiation
Volume7
Issue number8
StatePublished - 1996

Fingerprint

Fibroblasts
E2F Transcription Factors
Cyclin A
S Phase
Cyclin-Dependent Kinase Inhibitor p21
Cyclin D
Multiprotein Complexes
Cyclin E
Cell Cycle Proteins
Protein S
Proliferating Cell Nuclear Antigen
Diploidy
DNA Replication
Cell Proliferation
Gene Expression
DNA
Enzymes
Growth

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

A role for a p21-E2F interaction during senescence arrest of normal human fibroblasts. / Afshari, Cynthia A.; Nichols, Michael A.; Xiong, Yue; Mudryj, Maria.

In: Cell Growth and Differentiation, Vol. 7, No. 8, 1996, p. 979-988.

Research output: Contribution to journalArticle

Afshari, Cynthia A. ; Nichols, Michael A. ; Xiong, Yue ; Mudryj, Maria. / A role for a p21-E2F interaction during senescence arrest of normal human fibroblasts. In: Cell Growth and Differentiation. 1996 ; Vol. 7, No. 8. pp. 979-988.
@article{98cb106ebbbd49649abc43c31e3e8180,
title = "A role for a p21-E2F interaction during senescence arrest of normal human fibroblasts",
abstract = "The family of E2F transcription factors forms different multiprotein complexes with cell cycle regulatory proteins to control the expression of genes important in cell proliferation. In this study, we identified four distinct E2F complexes present in aged and senescent normal, human diploid fibroblasts. Two appeared to be identical to the previously described G1- specific p130 and Rb-E2F complexes present in young G0-arrested cells. The other two were novel E2F complexes that contained the cyclin-dependent kinase inhibitor p21 (cip1/WAF1/Sdi1/CAP20/PIC1) complexed with Rb/CDK2/cyclin E or with the Rb-related p107/CDK2/cyclin D. These p21-E2F complexes, while present in young G1 cells at very low levels, were elevated in senescent cells. The p21 containing E2F complexes were not detected during the S-phase in young cells. The DNA-binding stability of the p21 complexes was approximately 10 times greater than the stability of any other E2F complex or uncomplexed E2F. Addition of purified p21 protein to the S-phase-specific cyclin A/CDK2-p107-E2F complex from young cells dissociated cyclin A and CDK2 from p107/E2F, suggesting an additional novel function for p21. Finally, expression of p21 specifically inhibited transcription from an E2F-dependent promoter but had no effect on a mutant E2 promoter. In addition to its inhibition of CDK enzymes and proliferating cell nuclear antigen function in DNA replication, these studies reveal a novel mechanism by which p21 mediates growth arrest: direct interaction with E2F complexes and negative regulation of E2F transcription factor activity.",
author = "Afshari, {Cynthia A.} and Nichols, {Michael A.} and Yue Xiong and Maria Mudryj",
year = "1996",
language = "English (US)",
volume = "7",
pages = "979--988",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - A role for a p21-E2F interaction during senescence arrest of normal human fibroblasts

AU - Afshari, Cynthia A.

AU - Nichols, Michael A.

AU - Xiong, Yue

AU - Mudryj, Maria

PY - 1996

Y1 - 1996

N2 - The family of E2F transcription factors forms different multiprotein complexes with cell cycle regulatory proteins to control the expression of genes important in cell proliferation. In this study, we identified four distinct E2F complexes present in aged and senescent normal, human diploid fibroblasts. Two appeared to be identical to the previously described G1- specific p130 and Rb-E2F complexes present in young G0-arrested cells. The other two were novel E2F complexes that contained the cyclin-dependent kinase inhibitor p21 (cip1/WAF1/Sdi1/CAP20/PIC1) complexed with Rb/CDK2/cyclin E or with the Rb-related p107/CDK2/cyclin D. These p21-E2F complexes, while present in young G1 cells at very low levels, were elevated in senescent cells. The p21 containing E2F complexes were not detected during the S-phase in young cells. The DNA-binding stability of the p21 complexes was approximately 10 times greater than the stability of any other E2F complex or uncomplexed E2F. Addition of purified p21 protein to the S-phase-specific cyclin A/CDK2-p107-E2F complex from young cells dissociated cyclin A and CDK2 from p107/E2F, suggesting an additional novel function for p21. Finally, expression of p21 specifically inhibited transcription from an E2F-dependent promoter but had no effect on a mutant E2 promoter. In addition to its inhibition of CDK enzymes and proliferating cell nuclear antigen function in DNA replication, these studies reveal a novel mechanism by which p21 mediates growth arrest: direct interaction with E2F complexes and negative regulation of E2F transcription factor activity.

AB - The family of E2F transcription factors forms different multiprotein complexes with cell cycle regulatory proteins to control the expression of genes important in cell proliferation. In this study, we identified four distinct E2F complexes present in aged and senescent normal, human diploid fibroblasts. Two appeared to be identical to the previously described G1- specific p130 and Rb-E2F complexes present in young G0-arrested cells. The other two were novel E2F complexes that contained the cyclin-dependent kinase inhibitor p21 (cip1/WAF1/Sdi1/CAP20/PIC1) complexed with Rb/CDK2/cyclin E or with the Rb-related p107/CDK2/cyclin D. These p21-E2F complexes, while present in young G1 cells at very low levels, were elevated in senescent cells. The p21 containing E2F complexes were not detected during the S-phase in young cells. The DNA-binding stability of the p21 complexes was approximately 10 times greater than the stability of any other E2F complex or uncomplexed E2F. Addition of purified p21 protein to the S-phase-specific cyclin A/CDK2-p107-E2F complex from young cells dissociated cyclin A and CDK2 from p107/E2F, suggesting an additional novel function for p21. Finally, expression of p21 specifically inhibited transcription from an E2F-dependent promoter but had no effect on a mutant E2 promoter. In addition to its inhibition of CDK enzymes and proliferating cell nuclear antigen function in DNA replication, these studies reveal a novel mechanism by which p21 mediates growth arrest: direct interaction with E2F complexes and negative regulation of E2F transcription factor activity.

UR - http://www.scopus.com/inward/record.url?scp=0029827771&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029827771&partnerID=8YFLogxK

M3 - Article

C2 - 8853893

AN - SCOPUS:0029827771

VL - 7

SP - 979

EP - 988

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 8

ER -