XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence
Open accessAbstract
Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21 CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21 CIP1 expression to control senescence and tumorigenesis.
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OIS is characterized by the upregulation of CDK inhibitors, including p15INK4B, p16INK4A, p21CIP1, and an increased senescence-associated β-galactosidase (SA-β-Gal) activity.
“It is characterized by the upregulation of CDK inhibitors, including p15INK4B, p16INK4A, p21CIP1, and an increased senescence-associated β-galactosidase (SA-β-Gal) activity.285,286”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [286]
The paper’s background passage (labeled Abstract in our copy; page unavailable) identifies p21CIP1 and p16INK4a as CDK inhibitors upregulated during senescence. The Results section on TCF3 reports their induction during OIS and uses SA-β-Gal staining to assess senescence. Our copy does not establish the claimed upregulation of p15INK4B. (LLM, conf=0.87)
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References 39 · Cited by 30
- Authors
- Innes, A. J., Sun, B., Wagner, V., Brookes, S., McHugh, D., Pombo, J., Porreca, R. M., Dharmalingam, G., Vernia, S., Zuber, J., Vannier, J.-B., García-Escudero, R., & Gil, J.
- Affiliations
- MRC London Institute of Medical Sciences (GB)
- Research Institute of Molecular Pathology (AT)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2021-02-18
- Volume
- 35
- Issue
- 5-6
- Pages
- 379-391
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC7919420
- OpenAlex
- W3129990567
- Cited by
- 30
- References
- 39
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 2
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Genes & Development (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Medical Research Council (MC_U120085810)
- Worldwide Cancer Research (18-0215)
- Cancer Research UK (C15075/A28647)
- Chain-Florey Clinical Fellowship
- National Institute for Health Research
- NIHR
- NIHR Imperial Biomedical Research Centre
- MRC
- German Cancer Aid Mildred-Scheel-Postdoc Program
- ERC (637798)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- tumor suppressor, cellular senescence, p21, oncogene-induced senescence, replicative senescence, TCF3, nucleocytoplasmic shuttling, cyclin-dependent kinase inhibitors, liver cancer, carcinogenesis, overall survival
- MeSH terms
- Animals, Female, Humans, Neoplasms, Cellular Senescence, Gene Expression Regulation, Developmental, ran GTP-Binding Protein, Karyopherins, Telomeric Repeat Binding Protein 2, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Gene Knockdown Techniques
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