Effect of Y220C Mutation on p53 and Its Rescue Mechanism: A Computer Chemistry Approach

Rauf, Shah Md. Abdur; Endou, Akira; Takaba, Hiromitsu; Miyamoto, Akira

doi:10.1007/s10930-012-9458-x

Cited by 20 publications

(9 citation statements)

References 24 publications

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“…It has been proposed that the loss of DNA binding function of mutant p53 Y220C is due to the loss of hydrophobic interaction, creating a solvent-accessible cleft at the site of mutation that decreases its thermodynamic stability (69,70). Liu et al have shown that the binding of a small molecule, PK7088, to mutant p53 Y220C in Huh7 cells restored its transcription activity to a level similar to that of wild-type p53 (5).…”

Section: Discussionmentioning

confidence: 99%

FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53

Dixit

Pandey

Liu

et al. 2015

J Virol

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Hepatitis C virus (HCV) is a leading cause of chronic hepatitis C (CHC), liver cirrhosis, and hepatocellular carcinoma (HCC).Immunohistochemistry of archived HCC tumors showed abundant FBP1 expression in HCC tumors with the CHC background. Oncomine data analysis of normal versus HCC tumors with the CHC background indicated a 4-fold increase in FBP1 expression with a concomitant 2.5-fold decrease in the expression of p53. We found that FBP1 promotes HCV replication by inhibiting p53 and regulating BCCIP and TCTP, which are positive and negative regulators of p53, respectively. The severe inhibition of HCV replication in FBP1-knockdown Huh7.5 cells was restored to a normal level by downregulation of either p53 or BCCIP. Although p53 in Huh7.5 cells is transcriptionally inactive as a result of Y220C mutation, we found that the activation and DNA binding ability of Y220C p53 were strongly suppressed by FBP1 but significantly activated upon knockdown of FBP1. Transient expression of FBP1 in FBP1 knockdown cells fully restored the control phenotype in which the DNA binding ability of p53 was strongly suppressed. Using electrophoretic mobility shift assay (EMSA) and isothermal titration calorimetry (ITC), we found no significant difference in in vitro target DNA binding affinity of recombinant wild-type p53 and its Y220C mutant p53. However, in the presence of recombinant FBP1, the DNA binding ability of p53 is strongly inhibited. We confirmed that FBP1 downregulates BCCIP, p21, and p53 and upregulates TCTP under radiation-induced stress. Since FBP1 is overexpressed in most HCC tumors with an HCV background, it may have a role in promoting persistent virus infection and tumorigenesis. IMPORTANCEIt is our novel finding that FUSE binding protein 1 (FBP1) strongly inhibits the function of tumor suppressor p53 and is an essential host cell factor required for HCV replication. Oncomine data analysis of a large number of samples has revealed that overexpression of FBP1 in most HCC tumors with chronic hepatitis C is significantly linked with the decreased expression level of p53. The most significant finding is that FBP1 not only physically interacts with p53 and interferes with its binding to the target DNA but also functions as a negative regulator of p53 under cellular stress. FBP1 is barely detectable in normal differentiated cells; its overexpression in HCC tumors with the CHC background suggests that FBP1 has an important role in promoting HCV infection and HCC tumors by suppressing p53. H epatitis C virus (HCV) infection is a leading cause of chronic liver diseases. More than a decade after the identification of HCV as the major causative agent of non-A, non-B hepatitis (1), molecular strategies for complete eradication of HCV infection are actively pursued. HCV is the major cause of chronic liver disease. According to new findings from the U.S. Centers for Disease Control and Prevention (CDC), the number of individuals in the U.S. living with chronic hepatitis C virus infection is about 2.7 million (2). Globa...

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Section: Discussionmentioning

confidence: 99%

FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53

Dixit

Pandey

Liu

et al. 2015

J Virol

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“…For Y220C mutation of p53, it is reported that this mutation weakened the anti-tumoral ability of p53 through rapidly denaturing and aggregating p53 (refs. 25,26 ). Whereas, Hep3B cell line is a p53 natural deficiency cell line 27 .…”

Section: Resultsmentioning

confidence: 99%

MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53

Wang

Tan

et al. 2019

Oncogenesis

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Poor prognosis of hepatocellular carcinoma (HCC) patients is frequently associated with rapid tumor growth, recurrence and drug resistance. MT1G is a low-molecular weight protein with high affinity for zinc ions. In the present study, we investigated the expression of MT1G, analyzed clinical significance of MT1G, and we observed the effects of MT1G overexpression on proliferation and apoptosis of HCC cell lines in vitro and in vivo. Our results revealed that MT1G was significantly downregulated in tumor tissues, and could inhibit the proliferation as well as enhance the apoptosis of HCC cells. The mechanism study suggested that MT1G increased the stability of p53 by inhibiting the expression of its ubiquitination factor, MDM2. Furthermore, MT1G also could enhance the transcriptional activity of p53 through direct interacting with p53 and providing appropriate zinc ions to p53. The modulation of MT1G on p53 resulted in upregulation of p21 and Bax, which leads cell cycle arrest and apoptosis, respectively. Our in vivo assay further confirmed that MT1G could suppress HCC tumor growth in nude mice. Overall, this is the first report on the interaction between MT1G and p53, and adequately uncover a new HCC suppressor which might have therapeutic values by diminishing the aggressiveness of HCC cells.

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“…Cys182, Cys229, Cys242 and Cys277 are all exposed on the surface of the core domain, and are potential targets for modifications [64, 81]. According to Lambert et al mut-p53 is more amenable to this type of covalent modification than the wild-type version [80].…”

Section: Agents Restoring P53 Wild-type Conformationmentioning

confidence: 99%

The role of p53 in cancer drug resistance and targeted chemotherapy

et al. 2016

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Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53s regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.

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Effect of Y220C Mutation on p53 and Its Rescue Mechanism: A Computer Chemistry Approach

Cited by 20 publications

References 24 publications

FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53

FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53

MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53

The role of p53 in cancer drug resistance and targeted chemotherapy

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