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-8575121-B2
Publication Date
2013-11-05
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 by manipulating the expression and function of isoforms of the p53 tumor suppressor protein, specifically Δ133p53 and p53β. The discovery that switching expression from Δ133p53 to p53β induces replicative cellular senescence in normal human fibroblasts underlies these methods. Overexpression of p53β promotes senescence, while Δ133p53 inhibits it, allowing extended cell proliferation beyond normal senescence checkpoints.
The problem addressed is that cell senescence limits cell division and thus impacts aging, cancer, and tissue regeneration. Current understanding links p53 tumor suppressor activity to cellular senescence, but the regulation via p53 isoforms was unclear. The invention solves this by revealing a telomere-mediated mechanism where natural p53 isoforms modulate wild-type p53 activity, influencing replicative lifespan and cellular senescence. The invention leverages this mechanism to inhibit undesirable cellular proliferation, such as cancer, or to extend lifespan of cells for regenerative purposes.
Claims Coverage
The patent includes multiple independent claims focusing on methods of modulating cell senescence and cancer cell growth via agents targeting p53 isoforms. The main inventive features relate to use of agents that specifically inhibit or activate the functions or expressions of Δ133p53 or p53β isoforms, and their applications in cancer treatment, extending replicative lifespan, and tissue regeneration.
Use of agents inhibiting Δ133p53 to promote senescence and treat cancer
The method involves contacting cells, including cancer cells, with agents that inhibit the function or expression of Δ133p53 without affecting wild-type p53, thereby promoting senescence and inhibiting cancer cell growth. The agents can include siRNA, shRNA, or ribozymes specifically targeting Δ133p53.
Use of agents activating Δ133p53 to inhibit senescence and extend replicative lifespan
The method involves contacting cells with agents that activate the function or expression of Δ133p53 to inhibit cellular senescence and extend the replicative lifespan of cells. This can generate cell populations suitable for tissue regeneration and treating degenerative diseases.
Use of agents activating p53β to promote senescence and treat cancer
The method comprises contacting cancer cells with agents that activate the function or expression of p53β, thereby promoting senescence and inhibiting cancer cell growth. The agents can include nucleic acids encoding p53β or expression cassettes.
Use of agents inhibiting p53β to inhibit senescence and extend replicative lifespan
The method involves contacting cells with agents that inhibit the function or expression of p53β to inhibit senescence, extend replicative lifespan, and prevent or treat degenerative diseases. Inhibitory agents include antisense oligonucleotides, siRNA, shRNA, ribozymes, or small organic molecules specifically targeting p53β.
Use of agents inhibiting miR-34a to inhibit senescence and extend lifespan
The method comprises contacting cells with agents that inhibit the function or expression of miR-34a, such as antisense oligonucleotides, thereby inhibiting senescence and extending the replicative lifespan of cells.
Methods for generating cell populations for tissue regeneration
These involve contacting cells with agents that activate Δ133p53 or inhibit p53β to inhibit senescence, increase cell divisions, and culture cells to obtain populations for tissue regeneration useful for treating degenerative diseases.
Compositions comprising siRNA directed to Δ133p53 for promoting senescence
Such compositions include siRNA molecules, optionally shRNA, targeting Δ133p53 to promote senescence and inhibit undesirable cell proliferation, for use in cancer treatment.
Methods for identifying modulators of senescence acting on Δ133p53 or p53β
These methods include contacting candidate compounds with samples comprising Δ133p53 or p53β and determining functional effects such as changes in cell proliferation, cell cycle arrest, or apoptosis to identify activators or inhibitors that modulate senescence, enabling therapeutic applications.
The independent claims cover methods and compositions for specifically modulating the activity or expression of p53 isoforms Δ133p53 and p53β to control cellular senescence and proliferation, with applications in cancer treatment, aging, and tissue regeneration. The claims emphasize specificity to isoforms and include various molecular agents such as siRNA, antisense oligonucleotides, and small molecules.
Stated Advantages
Providing methods to promote senescence specifically in cells to inhibit cancer cell growth without affecting wild-type p53 activity.
Extending replicative lifespan of cells by inhibiting senescence, enabling generation of cell populations for tissue regeneration.
Offering new therapeutic approaches for treating diseases associated with inadequate senescence or undesirable cell proliferation, including cancers and degenerative diseases.
Documented Applications
Methods and compositions for treating or preventing cancer by promoting senescence in cancer cells via inhibition of Δ133p53.
Generating cell populations with extended replicative lifespan for use in tissue regeneration and treating age-related degenerative diseases such as osteoporosis, osteoarthritis, macular degeneration, and atherosclerosis.
Enhancing or restoring immune function by extending T cell lifespan through modulation of p53 isoforms and miR-34a.
Screening methods for identifying compounds that modulate senescence by affecting Δ133p53 or p53β function or expression, useful for cancer prevention or lifespan extension.
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