The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
ΔNp63α Is an Oncogene that Targets Chromatin Remodeler Lsh to Drive Skin Stem Cell Proliferation and Tumorigenesis
Open accessAbstract
SUMMARY The p53 homolog p63 is essential for development, yet its role in cancer is not clear. We discovered that p63 deficiency evokes the tumor suppressive mechanism of cellular senescence, causing a striking absence of stratified epithelia such as the skin. Here we identify the predominant p63 isoform, ΔNp63α, as a protein that bypasses oncogene induced senescence to drive tumorigenesis in vivo. Interestingly, bypass of senescence promotes stem-like proliferation and maintains survival of the keratin 15-positive stem cell population. Furthermore, we identify the chromatin remodeling protein Lsh as a new target of ΔNp63α that is an essential mediator of senescence bypass. These findings indicate that ΔNp63α is an oncogene that cooperates with Ras to promote tumor-initiating stem-like proliferation, and suggest that Lsh-mediated chromatin remodeling events are critical to this process.
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“Specific TFs were also essential, including TP63, the epidermal master regulator and cSCC oncogene (Keyes et al., 2011), as well as the AP1 family TFs, FOSL1 and JUNB.”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Keyes et al., 2011
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Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 1×
“As shown previously, Ras induced features of senescence, including proliferation arrest, a characteristic morphology, and enhanced senescence-associated b-galactosidase (SA-b-gal) activity (Figure 1; Serrano et al., 1997).”
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Butel, J. S., & Bradley, A. (1992) · Nature · doi:10.1038/356215a0 · Cited by 4,649 · cited 1×
“In contrast to the viable and fertile, yet tumor-prone, phenotype of p53-deficient mice (Donehower et al., 1992; Jacks et al., 1994), p63-deficient mice die postnatally from severe developmental anomalies, including a lack of skin and associated derivatives, an absence of glands such as prostate and breast, and trunca…”
p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development
Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C. J., Sharpe, A. H., Caput, D., Crum, C. P., et al. (1999) · Nature · doi:10.1038/19539 · Cited by 2,264
Crypt stem cells as the cells-of-origin of intestinal cancer
Barker, N., Ridgway, R. A., van Es, J. H., van de Wetering, M., Begthel, H., van den Born, M., Danenberg, E., Clarke, A. R., Sansom, O. J., & Clevers, H. C. (2008) · Nature · doi:10.1038/nature07602 · Cited by 2,232 · cited 1×
“In some tumors, the cell of origin is suggested to be a normal somatic stem cell that has acquired mutations that allow it to transform (Barker et al., 2009).”
Yang, A., Kaghad, M., Wang, Y., Gillett, E. S., Fleming, M. D., Dötsch, V., Andrews, N. C., Caput, D., & McKeon, F. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80275-0 · Cited by 2,118
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051
Defining the Epithelial Stem Cell Niche in Skin
Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E., Rendl, M., & Fuchs, E. (2004) · Science · doi:10.1126/science.1092436 · Cited by 2,031 · cited 1×
“Genes whose expression is elevated in the keratinocyte stem cell populations of mouse skin have been identified (Blanpain et al., 2004; Mignone et al., 2007; Tumbar et al., 2004).”
p63 is a p53 homologue required for limb and epidermal morphogenesis
Mills, A. A., Zheng, B., Wang, X., Vogel, H. S., Roop, D. R., & Bradley, A. (1999) · Nature · doi:10.1038/19531 · Cited by 2,015 · cited 1×
“, 1994), p63-deficient mice die postnatally from severe developmental anomalies, including a lack of skin and associated derivatives, an absence of glands such as prostate and breast, and truncation of limbs (Mills et al., 1999; Yang et al., 1999).”
Self-citationEpigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?
Baylin, S. B., & Ohm, J. E. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1799 · Cited by 1,657
Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML
Jamieson, C. H. M., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040258 · Cited by 1,485
Cited by
Sorted by citations
Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma
Ji, A. L., Rubin, A. J., Thrane, K., Jiang, S., Reynolds, D. L., Meyers, R. M., Guo, M. G., George, B. M., Mollbrink, A., Bergenstråhle, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.039 · Cited by 1,117
“Specific TFs were also essential, including TP63, the epidermal master regulator and cSCC oncogene (Keyes et al., 2011), as well as the AP1 family TFs, FOSL1 and JUNB.”
BackgroundSenescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798
Wang, M., Mao, C., Ouyang, L., Liu, Y., Lai, W., Liu, N., Shi, Y., Chen, L., Xiao, D., Yu, F., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0304-y · Cited by 530
Nowell, C. S., & Radtke, F. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.145 · Cited by 379
Andricovich, J., Perkail, S., Kai, Y., Casasanta, N., Peng, W., & Tzatsos, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.02.003 · Cited by 320
“A molecular hallmark of the “C2-squamous-like” subtype is strong upregulation of the ΔNp63 isoform which has been linked to squamous identity (Hoadley et al., 2014; Keyes et al., 2011).”
Background
Metadata
- Authors
- Keyes, W. M., Pecoraro, M., Aranda, V., Vernersson-Lindahl, E., Li, W., Vogel, H., Guo, X., Garcia, E. L., Michurina, T. V., Enikolopov, G., Muthuswamy, S. K., & Mills, A. A.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Universitat Pompeu Fabra (ES)
- Stanford Medicine (US)
- University of Toronto (CA)
- Corresponding author
- Keyes, William M.
- Mills, Alea A.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 8
- Issue
- 2
- Pages
- 164-176
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4373450
- OpenAlex
- W2005062632
- Semantic Scholar
- c1f79d43c5cb2d63b4b44bf6992e804b60c11dd7
- Cited by
- 193
- References
- 53
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 11 · 2023: 8 · 2022: 5 · 2021: 14 · 2020: 12 · 2019: 14 · 2018: 13 · 2017: 17 · 2016: 18 · 2015: 6 · 2014: 18 · 2013: 18 · 2012: 17
- FWCI
- 14.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, other-oa)
- Funders
- National Cancer Institute (R01CA098830)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- ΔNp63α, p63 isoforms, LSH, chromatin remodeling, oncogenes, senescence bypass, oncogene-induced senescence, skin stem cells, keratin 15, stem cell proliferation, carcinogenesis, stratified epithelium, skin cancer
- MeSH terms
- Animals, Cells, Cultured, DNA Helicases, Flow Cytometry, Humans, Mice, Nude, Phosphoproteins, Protein Binding, Skin, Stem Cells, Trans-Activators, Keratinocytes, Polymerase Chain Reaction, Chromatin Immunoprecipitation, Cell Proliferation, Mice
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