Human p53 Mutations and a Genetic System in Yeast for Functional Identification of Human p53 Mutations
Description of Invention:
The tumor suppressor gene p53, a key regulator of cellular mechanisms that maintain genome integrity, is the most commonly inactivated gene target associated with neoplastic transformation. p53 is mutated in about 50% of all human tumors and more than 80% of these mutations are missense, leading to single amino acid changes. This invention relates to human p53 mutants and identification methods using screening assays in the yeast Saccharomyces cerevisiae to functionally categorize expressed p53 mutant proteins at varying levels of expression towards several human target response sequences. Additionally, the invention relates to methods of detecting or generating novel human p53 mutations with properties that can include toxicity in yeast and growth suppression in human cells, enhanced or reduced transactivation relative to wildtype p53, altered promoter selectivity, and reactivation by mutation or chemical modification of common tumor mutations for the transactivation function of major p53 downstream genes. In particular, the inventors have discovered a V122A p53 mutation exhibits strong cell proliferation inhibition. This feature suggests that p53 alleles such as V122A might be valuable both for functional studies of p53-regulated cellular responses and possibly for p53 based cancer gene therapy.
Applications:
Cancer therapeutics
Model to screen for small molecules or peptides that can modify p53 functions
Pharmaceutical screen for p53 drug modifiers
Market:
An estimated 1,444,920 new cancer diagnoses in the U.S. in 2007
Cancer drug market is estimated to be $50 billion a year in 2010
Development Status:
The technology is currently in the pre-clinical stage of development.
Inventors:
Michael A. Resnick and Alberto Inga (NIEHS)
Patent Status:
DHHS Reference No. E-183-1999/0 --
U.S. Patent No. 7,256,260 issued 14 Aug 2007
U.S. Patent Application No. 11/893,037 filed 14 Aug 2007
International filings in Europe, Australia, Canada, and Japan
Relevant Publication:
A Jegga, A Inga, D Menendez, BJ Aronow, MA Resnick. Functional evolution of the p53 regulatory network through its target response elements. Proc Natl Acad Sci. USA. 2008 Jan 22;105(3):944-949. [PubMed abs]
MM Horvath, X Wang, MA Resnick, DA Bell. Divergent evolution of human p53 binding sites: cell cycle versus apoptosis. PLoS Genet. 2007 Jul;3(7):1284-1295. [PubMed abs]
D Menendez, A Inga, J Snipe,O Krysiak, G Schönfelder, MA Resnick. A singlenucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1. Mol Cell Biol. 2007 Apr;27(7):2590-2600. [PubMed abs]
P Monti, Y Ciribilli, J Jordan, P Menichini, DM Umbach, MA Resnick, L Luzzato, A Inga, G Fronza. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Can Res. 2006 Jul 1;13(13):3789-3795. [PubMed abs]
D Menendez, A Inga, J Jordan, MA Resnick. Changing the p53 master regulatory network: ELEMENTary, my dear Mr. Watson. Oncogene. 2007 Apr 2;26(15):2191-2201. [PubMed abs]
D Menendez, A Inga, J Jordan, MA Resnick. The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes. Mol Cell Biol. 2006 Mar;26(6):2297-2308. [PubMed abs]
DJ Tomso, A Inga, D Menendez, G Pittman, M Campbell, D Bell, MA Resnick. Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation. Proc Natl Acad Sci USA. 2005 May 3;102(18):6431-6436. [PubMed abs]
MA Resnick and A Inga. Functional mutations in the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc Nat Acad Sci USA. 2003 Aug 19;100(17):9934-9939. [PubMed abs]
A Inga, F Storici, TA Darden, MA Resnick. Differential transactivation by the p53 transcription factor is highly dependent on p53 level and promoter target sequence. Mol Cell Biol. 2002 Dec;22(24):8612-8625, 2002. [PubMed abs]
Licensing Status: Available for exclusive or non-exclusive licensing.
Portfolios: Gene Based Therapies Cancer
Cancer -Diagnostics-In Vitro Cancer -Diagnostics Gene Based Therapies -Diagnostics
For Additional Information Please Contact: Jennifer Wong
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301)435-4633
Email: wongje@mail.nih.gov
Fax: (301)402-0220
