Tag: p53

Author: Wade, Mark; Li, Yao-Cheng; Wahl, Geoffrey M. Description: The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress…

Author: Carlsen, Lindsey; Zhang, Shengliang; Tian, Xiaobing; De La Cruz, Arielle; George, Andrew; Arnoff, Taylor E.; El-Deiry, Wafik S. Description: p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1;…

Author: Olukunle, Oluwatoyin Folake; Olowosoke, Christopher Busayo; Khalid, Aqsa; Oke, Grace Ayomide; Omoboyede, Victor; Umar, Haruna Isiyaku; Ibrahim, Ochapa; Adeboboye, Covenant Femi; Iwaloye, Opeyemi; Olawale, Femi; Adedeji, Ayodeji Adeola; Bello, Taye; Alabere, Hafsat Olateju; Chukwuemeka, Prosper Obed Description: Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells….

Author: Bykov, Vladimir J. N.; Issaeva, Natalia; Zache, Nicole; Shilov, Alexandre; Hultcrantz, Monica; Bergman, Jan; Selivanova, Galina; Wiman, Klas G. Description: Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3…

Author: Lambert, Jeremy M. R.; Gorzov, Petr; Veprintsev, Dimitry B.; Soderqvist, Maja; Segerback, Dan; Bergman, Jan; Fersht, Alan R.; Hainaut, Pierre; Wiman, Klas G.; Bykov, Vladimir J. N. Description: Restoration of wild-type p53 expression triggers cell death and eliminates tumors in vivo. The identification of mutant p53-reactivating small molecules such as PRIMA-1 opens possibilities for the development of more efficient anticancer drugs. Although the biological effects of PRIMA-1 are well demonstrated, little is known about its molecular mechanism of action. We show here that PRIMA-1 is converted to compounds that…

Author: Mandinova, Anna; Lee, Sam W. Description: A large fraction of human tumors carry p53 mutations, which allow tumor initiation and progression; furthermore, it is now clear that restoration or reactivation of wild-type p53 function prompts rapid elimination of tumors. The discovery and design of compounds that reactivate or enhance the p53 pathway has resulted in the identification of promising drug candidates that have now entered clinical trials for anticancer strategies. However, some of these agents appear to elicit undesirable toxic effects on normal cells and tissues and therefore are…

Author: Graves, Bradford; Thompson, Thelma; Xia, Mingxuan; Janson, Cheryl; Lukacs, Christine; Deo, Dayanand; Di Lello, Paola; Fry, David; Garvie, Colin; Huang, Kuo-Sen; Gao, Lin; Tovar, Christian; Lovey, Allen; Wanner, Jutta; Vassilev, Lyubomir T. Description: Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small…