Therapeutic applications of P53 isoforms in regenerative medicine, aging and cancer
Inventors
Harris, Curtis C. • Fujita, Kaori • Horikawa, Izumi • Vojtesek, Borivoj • Bourdon, Jean-Christophe • Lane, David P.
Assignees
Masaryk Memorial Cancer Institute • University of Dundee • US Department of Health and Human Services
Publication Number
US-9068165-B2
Publication Date
2015-06-30
Expiration Date
2028-10-21
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Abstract
The present invention provides methods and compositions for modulating cell senescence and cell proliferation using isoforms of the p53 tumor suppressor protein. The methods and compositions of the invention find use in inhibiting cancer cell growth or in generating populations of cells for tissue regeneration through the modulation of cell senescence and proliferation.
Core Innovation
The invention provides methods and compositions for modulating cell senescence and cell proliferation through the use of isoforms of the p53 tumor suppressor protein, specifically Δ133p53 and p53β. This modulation can be applied to inhibit cancer cell growth or to generate populations of cells for tissue regeneration by managing cellular senescence and proliferation states.
The problem addressed is the limitation imposed by cellular senescence, where normal human cells enter irreversible growth arrest after a finite number of divisions—known as the Hayflick limit—and the difference between normal cells and cancer cells in bypassing this state. Given that cellular senescence involves mechanisms including telomere shortening, INK4a/ARF derepression, and DNA damage, all implicating p53 function, the invention identifies a need for methods to manipulate these processes for therapeutic benefit in aging, regenerative medicine, and cancer treatment.
The invention is based on the discovery that switching expression from Δ133p53 to p53β induces replicative cellular senescence in human fibroblasts. p53β promotes senescence, while Δ133p53 inhibits it; knockdown of Δ133p53 induces senescence. Δ133p53 represses wild-type p53 transcriptional targets, such as p21WAF1 and miR-34a, and inhibits p53-mediated degradation of the telomere-binding protein TRF2, thus permitting proliferation beyond the typical senescence checkpoint. Therefore, the invention exploits a telomere-mediated regulatory mechanism of cellular senescence by modulation of p53 isoforms.
Claims Coverage
The patent includes one independent claim focused on a method for extending the replicative lifespan of a cell using Δ133p53.
Method of extending replicative lifespan by activating Δ133p53
A method comprising contacting a cell with an agent that activates the function or expression of Δ133p53 to inhibit cell senescence and extend replicative lifespan, where the agent includes a polynucleotide encoding Δ133p53 or an expression cassette thereof.
The claims cover methods of extending cellular replicative lifespan by inhibiting senescence through activation of Δ133p53 via nucleic acid-based agents, encompassing various cell types including human cells, tissue regeneration cells, and T cells, and applications in degenerative diseases, particularly when wild-type p53 is present.
Stated Advantages
Provides methods to inhibit cancer cell growth by promoting cellular senescence via modulation of p53 isoforms.
Enables generation of cell populations for tissue regeneration by extending replicative lifespan through inhibition of senescence.
Offers therapeutic approaches for treating degenerative diseases and age-related conditions by manipulating cell senescence.
Supplies a novel mechanism to regulate cell senescence by leveraging natural p53 isoforms to either promote or inhibit senescence.
Documented Applications
Inhibiting cancer cell growth by promoting senescence in cancer cells through Δ133p53 inhibition or p53β activation.
Generating populations of cells for tissue regeneration by extending replicative lifespan via activation of Δ133p53 or inhibition of p53β.
Treating degenerative diseases such as osteoporosis, osteoarthritis, macular degeneration, and atherosclerosis by modulating senescence with p53 isoform-targeting agents.
Enhancing or restoring immune functions by extending T cell lifespan through modulation of Δ133p53, p53β, or miR-34a.
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