Primary and Compensatory Roles for RB Family Members at Cell Cycle Gene Promoters That Are Deacetylated and Downregulated in Doxorubicin-Induced Senescence of Breast Cancer Cells
Open accessAbstract
When treated with DNA-damaging chemotherapy agents, many cancer cells, in vivo and in vitro, undergo a terminal growth arrest and acquire a senescence-like phenotype. We investigated the molecular basis for this in breast cancer cells following a 2-hour treatment with 1 muM doxorubicin. Treated cells arrested in G1 and G2 phases of the cell cycle, with concomitant reductions in S-phase and G2-M regulatory genes. p53 and p21 protein levels increased within hours after treatment and were maintained for 5 to 6 days but were reduced 8 days posttreatment, though the cells remained growth arrested. Levels of p130 rose after drug treatment, and it was the primary RB family member recruited to the S-phase promoters cyclin A and PCNA and G2-M promoters cyclin B and cdc2, remaining present for the entire 8-day time period. In contrast, p107 protein and promoter occupancy levels declined sharply after drug treatment. RB was recruited to only the PCNA promoter. In MCF-7 cells with p130 knockdown, p107 compensated for p130 loss at all cell cycle gene promoters examined, allowing cells to retain the growth arrest phenotype. Cells with p130 and p107 knockdown similarly arrested, while cells with knockdown of all three family members failed to downregulate cyclin A and cyclin B. These results demonstrate a mechanistic role for p130 and compensatory roles for p107 and RB in the long-term senescence-like growth arrest response of breast cancer cells to DNA damage.
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RB is important for p53-dependent downregulation of multiple genes.
“RB, too, is important for p53-dependent downregulation of multiple genes.100, 101, 102, 103”
From Census and evaluation of p53 target genes (2017) · cites this paper as [101]
Cites
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
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“Indeed, one group has found that RB mediates different modifications of chromatin in senescent versus quiescent cells (27).”
BackgroundMethodInfluentialThe Rb/E2F pathway: expanding roles and emerging paradigms
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Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin
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p130/E2F4 Binds to and Represses the cdc2 Promoter in Response to p53
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Census and evaluation of p53 target genes
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Genetic compensation: A phenomenon in search of mechanisms
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Self-citationSASP: Tumor Suppressor or Promoter? Yes!
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Self-citationThe transcription factor p53: Not a repressor, solely an activator.
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Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival
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- Authors
- Jackson, J. G., & Pereira-Smith, O. M.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Texas Health Science Center at San Antonio, Department of Cellular and Structural Biology, Sam and Ann Barshop Institute for Longevity and Aging Studies, STCBM Building, 15355 Lambda Drive, San Antonio, Texas 78245-3207
- Corresponding author
- Jackson, James G.
- ORCID
- Jackson, James G.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-04-01
- Volume
- 26
- Issue
- 7
- Pages
- 2501-2510
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1430319
- OpenAlex
- W2136919190
- Cited by
- 108
- References
- 7
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 2 · 2018: 3 · 2017: 9 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 8
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Ellison Medical Foundation
- University of Texas Health Science Center at San Antonio
- National Institute on Aging (P01AG2752)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- retinoblastoma protein family, p130, p107, Rb, doxorubicin, chemotherapy-induced senescence, DNA damage response, cell cycle arrest, cyclin A, cyclin B, PCNA, cdc2, p53, p21, promoter binding, histone deacetylation, gene downregulation, compensatory function, breast cancer cells, MCF-7 cells
- MeSH terms
- Acetylation, Breast Neoplasms, Doxorubicin, Multigene Family, Histones, Humans, Promoter Regions, Genetic, Proteins, RNA, Messenger, Tumor Cells, Cultured, Down-Regulation, Tumor Suppressor Protein p53, Retinoblastoma Protein, G1 Phase, G2 Phase, S Phase, Cellular Senescence, Genes, cdc, Gene Expression Profiling, Retinoblastoma-Like Protein p130, Retinoblastoma-Like Protein p107
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