PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain
نویسندگان
چکیده
منابع مشابه
PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein.
Mutation of the p53 tumor suppressor gene is a common event in many types of tumors, including breast cancers. Mutant p53 (mtp53) protein is thought to promote tumor cell survival and resistance to chemotherapeutic drugs. Therefore, restoring p53 function by converting existing mtp53 to the wild-type p53 (wtp53) conformation is being pursued as one strategy to promote apoptosis of tumor cells. ...
متن کاملThermodynamic stability of wild-type and mutant p53 core domain.
Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads ...
متن کاملPRIMA-1MET Inhibits Growth of Mouse Tumors Carrying Mutant p53
Reactivation of the tumor suppressor activity to mutant p53 should trigger massive apoptosis and eliminate tumors. The low molecular weight compounds PRIMA-1 and the structural analog PRIMA-1MET reactivate human mutant p53 in vitro and suppress growth of human tumor xenografts in SCID mice. However, little is known about their effect on mouse mutant p53 in mouse tumor cells. We have examined th...
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The core domain of the tumour suppressor p53 is of inherently low thermodynamic stability and also low kinetic stability, which leads to rapid irreversible denaturation. Some oncogenic mutations of p53 act by just making the core domain thermosensitive, and so it is the target of novel anti-cancer drugs that bind to and stabilise the protein. Increasing the stability of the unstable core domain...
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p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in...
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ژورنال
عنوان ژورنال: Cancer Cell
سال: 2009
ISSN: 1535-6108
DOI: 10.1016/j.ccr.2009.03.003