Cited by 230Cancer-related Molecular PathwaysProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

Arrest of G 1 -S Progression by the p53-Inducible Gene PC3 Is Rb Dependent and Relies on the Inhibition of Cyclin D1 Transcription

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Guardavaccaro, Daniele, Corrente, Giuseppina, Covone, Francesca, Micheli, Laura, D'Agnano, Igea, Starace, Giuseppe, Caruso, Maurizia, Tirone, Felice·2000·Molecular and Cellular Biology

Abstract

The p53-inducible gene PC3 (TIS21, BTG2) is endowed with antiproliferative activity. Here we report that expression of PC3 in cycling cells induced accumulation of hypophosphorylated, growth-inhibitory forms of pRb and led to G(1) arrest. This latter was not observed in cells with genetic disruption of the Rb gene, indicating that the PC3-mediated G(1) arrest was Rb dependent. Furthermore, (i) the arrest of G(1)-S transition exerted by PC3 was completely rescued by coexpression of cyclin D1 but not by that of cyclin A or E; (ii) expression of PC3 caused a significant down-regulation of cyclin D1 protein levels, also in Rb-defective cells, accompanied by inhibition of CDK4 activity in vivo; and (iii) the removal from the PC3 molecule of residues 50 to 68, a conserved domain of the PC3/BTG/Tob gene family, which we term GR, led to a loss of the inhibition of proliferation as well as of the down-regulation of cyclin D1 levels. These data point to cyclin D1 down-regulation as the main factor responsible for the growth inhibition by PC3. Such an effect was associated with a decrease of cyclin D1 transcript and of cyclin D1 promoter activity, whereas no effect of PC3 was observed on cyclin D1 protein stability. Taken together, these findings indicate that PC3 impairs G(1)-S transition by inhibiting pRb function in consequence of a reduction of cyclin D1 levels and that PC3 acts, either directly or indirectly, as a transcriptional regulator of cyclin D1.

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Crossref · 10.1128/mcb.20.5.1797-1815.2000

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  • BTG2 can induce G1/S cell cycle arrest.

    “The p53 target genes BTG236, 154, 155 and GADD45A13, 156 can also induce G1/S and G2/M cell cycle arrest, respectively.”

    From Census and evaluation of p53 target genes (2017) · cites this paper as [154]

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Authors
Guardavaccaro, D., Corrente, G., Covone, F., Micheli, L., D'Agnano, I., Starace, G., Caruso, M., & Tirone, F.
Affiliations
  • Institute of Neurobiology and Molecular Medicine (IT)
  • Istituto di Tecnologie Biomediche
  • Istituto di Medicina Sperimentale
  • National Research Council (IT)
Venue
Molecular and Cellular Biology
Published
2000-03
Volume
20
Issue
5
Pages
1797-1815
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W1980093005
Cited by
230
References
124
Citations by year
2026: 2 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 1 · 2020: 1 · 2019: 6 · 2018: 10 · 2017: 3 · 2016: 11 · 2015: 12 · 2014: 7 · 2013: 7 · 2012: 15
FWCI
7.19
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
PC-3 cells, BTG2, G1/S transition, cell cycle arrest, retinoblastoma protein, cyclin D1, CDK4, transcriptional regulation, antiproliferative activity, growth inhibition
MeSH terms
Animals, Cell Cycle, Gene Expression Regulation, Transcription, Genetic, Tumor Suppressor Protein p53, Retinoblastoma Protein, G1 Phase, S Phase, Aspartic Acid Endopeptidases, 3T3 Cells, Cyclin D1, Proprotein Convertases, Mice

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