Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence
Open accessAbstract
Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16(INK4a), which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence.
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Cellular senescence serves as a fail-safe mechanism against the transforming activity of antiapoptotic oncogenes.
“Another tumor suppressor response, called cellular senescence, serves as a fail-safe mechanism against the transforming activity of antiapoptotic oncogenes (29, 40, 43).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [29]
The Abstract describes senescence as a program that prevents expansion of cells bearing oncogenic mutations, and the Discussion says STAT5A-induced senescence helps prevent cell transformation. Our copy does not characterize the oncogenes in this finding as antiapoptotic, so it supports the fail-safe point but not that specific qualifier. The supplied passages have no page numbers. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe pathway activated by p53 or Rb converges into a common senescence effector mechanism that has yet to be identified.
“This well-known fact (28, 29, 43, 48) indicates that the pathway activated by p53 or Rb converges into a common senescence effector mechanism that has yet to be identified.”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [29]
The Discussion and Figure 6 describe p53 and Rb as independently connected to the senescence program in STAT5A-induced senescence. That supports their ability to produce the same outcome, but the paper does not establish that they converge on a common, unidentified effector mechanism; its stated uncertainty concerns how the pathways connect to oncogenes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe shRNA against p53 or E7 did not rescue the senescence phenotype.
“Of note, as reported before (28, 29, 43, 48), the shRNA against neither p53 nor E7 rescued the senescence phenotype (see Fig. S3 in the supplemental material)”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [29]
The Results (page unavailable) state that in IMR90 fibroblasts, inactivating either the p53 or Rb pathway alone did not bypass Ras- or STAT5-induced senescence. They report experiments using E6 or CDK4, not shRNA against p53 or E7, so the specific interventions in the claim are not supported by this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRas-induced senescence in human cells can be mediated by either the p53 or the Rb family of tumor suppressors.
“Ras-induced senescence in human cells can be mediated by either the p53 or the Rb family of tumor suppressors (28, 29, 43, 48).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [29]
These mitochondrial changes appeared before the senescence cell cycle arrest and were totally prevented by disabling the p53 and Rb tumor suppressors.
“These changes appeared before the senescence cell cycle arrest and were totally prevented by disabling the p53 and Rb tumor suppressors, which are known to regulate independently the senescence effector mechanism (28, 29, 43, 48).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [29]
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Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
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Cited by
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Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence
Moiseeva, O., Bourdeau, V., Roux, A., Deschênes-Simard, X., & Ferbeyre, G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01868-08 · Cited by 408 · see citing works
Self-citationCellular Senescence in Postmitotic Cells: Beyond Growth Arrest
Sapieha, P., & Mallette, F. A. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.03.003 · Cited by 193 · see citing works
Self-citationIL-6-STAT3 signaling and premature senescence
Kojima, H., Inoue, T., Kunimoto, H., & Nakajima, K. (2013) · JAK-STAT · doi:10.4161/jkst.25763 · Cited by 170 · see citing works
- Authors
- Mallette, F. A., Gaumont-Leclerc, M.-F., Huot, G., & Ferbeyre, G.
- Affiliations
- Université de Montréal (CA)
- Corresponding author
- Ferbeyre, Gerardo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 282
- Issue
- 48
- Pages
- 34938-34944
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2140033176
- Cited by
- 51
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 6 · 2012: 3
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- oncogene-induced senescence, STAT5A, Rb pathway, p53, CDK4, proteasomal degradation, p21, p16INK4a, cyclin-dependent kinases, senescence bypass
- MeSH terms
- Cell Line, Cell Nucleus, Fibroblasts, Humans, Models, Biological, Signal Transduction, Down-Regulation, Tumor Suppressor Protein p53, Retinoblastoma Protein, Proto-Oncogene Proteins c-myc, Cellular Senescence, Tumor Suppressor Proteins, Cell Line, Tumor, Proteasome Endopeptidase Complex, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, STAT5 Transcription Factor, Cyclin-Dependent Kinase 4
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