Special Issue "The p53 Pathway in Cancers"

Quicklinks

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Yun Yen (Website)

Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, CA 91010, USA
Interests: cancer biology; drug discovery; biomarker; medical oncology; translational medicine

Special Issue Information

Dear Colleagues,

Deletion or mutations of TP53 gene is one of the most common genetic abnormalities in cancer. Since its discovery in 1979, the molecular and biological functions of p53 in cancer have been studied intensively. P53 senses stress signals such as DNA damage, activated oncogenes, nutrient deprivation, hypoxia, telomere attrition, oxidative stress and ribosome dysfunction. In response to potent stress signals, p53 triggers cell-cycle arrest, apoptosis and senescence to limit expansion of irreparable damaged or malignant cells. Under low-stress condition, p53 elicits responses such as DNA repair and antioxidation to promote survival and maintain genomic stability. Moreover, p53 also regulates angiogenesis, migration, metabolism and autophagy to restrict development of tumor. All these tumor suppressive activities mainly rely on transcription activation by p53, although p53 has other biochemical functions such as transcriptional repression and promotion of apoptosis by direct interaction with apoptotic regulators in the cytosol. The N-terminus of p53 contains two transcriptional activation domains (TADs), TAD1 (residues 1-40) and TAD2 (residues 40-60) which recruits both basal transcriptional machinery and co-activator complexes. The central core domain of p53 (residues 100-300) lies the DNA binding domain that direct the protein to p53-response elements (p53 RE). Most of the cancer associated p53 mutations are missense mutations in the DNA binding domain. The six most common p53 amino acid mutations in cancer (also known as “hotspots”) are R175, G245, R248, R249, R273 and R282. Other than inability to bind to DNA, these p53 mutants can confer gain of function which is linked to invasion and metastasis of cancer. Biological setting such as cell type and the nature of the stress determines the cell fate and transcriptional programs that are triggered by p53. In response to overt stress, apoptotic genes such as BAX, FAS, NOXA and PUMA or senescence genes such as CIP1, PAI1 and PML are activated to eradicate potentially oncogenic cells. Under lower stress conditions, DNA repair genes such as RRM2B, or antioxidatant genes such as SESN1, SESN2 and GPX1 are up-regulated to protect genome integrity. In addition, p53 inhibits glycolysis through TIGAR, promotes oxidative phosphorylation via SCO2 and blocks angiogenesis by activation of TSP-1. More than 125 direct p53-target genes have been identified and chromotin immunoprecipitation (ChIP) assays identified thousands of p53-binding sites on the genome. However, none of the p53-target gene knockout mouse model to date recapitulates the high tumor-penetrance and short tumor-latency in TP53 knockout mice suggesting that multiple p53-target genes controls tumor suppressive function by p53 in concert. In general, tumor cells containing functional p53 are more sensitive to radiation therapy or chemotherapy. However, recent evidence suggested that wild type p53 can engage into a pro-survival pathway to counteract apoptosis in some cases. Nevertheless, reactivation or restoration of functional p53 has been an attractive approach of chemotherapy and under development in the recent years. The strategies includes stabilization of wild type p53 such as inhibiting the activity of MDM2, an E3 ubiquitin ligase of p53 and interference of MDM2-p53 interaction; enhancement of DNA binding activity of wild type p53 by inactivating SIRT1 deacetylase as well as targeting mutant p53 to restore native conformation and transcription activation. Several small molecules have been discovered based on these approaches and are under investigation to test their efficacy as anti-cancer agents. Further studies on p53 mechanism of action and functional role in cancer will continue. These advances of knowledge will be helpful to gain insights on rational design of p53-based therapy in the future.

Prof. Dr. Yun Yen
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • P53 and DNA damage repair
  • P53 mutation
  • P53 and carcinogenesis
  • P53 and signaling
  • P53 and senescence

Published Papers (2 papers)

View options order results:
result details:
Displaying articles 1-2
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex
Cancers 2014, 6(1), 166-178; doi:10.3390/cancers6010166
Received: 22 November 2013 / Revised: 10 January 2014 / Accepted: 13 January 2014 / Published: 21 January 2014
Cited by 2 | PDF Full-text (1110 KB) | HTML Full-text | XML Full-text
Abstract
Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 [...] Read more.
Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53−/− cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53+/+ cells but not in p53−/− cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach. Full article
(This article belongs to the Special Issue The p53 Pathway in Cancers)

Review

Jump to: Research

Open AccessReview HEXIM1, a New Player in the p53 Pathway
Cancers 2013, 5(3), 838-856; doi:10.3390/cancers5030838
Received: 27 May 2013 / Revised: 24 June 2013 / Accepted: 24 June 2013 / Published: 4 July 2013
Cited by 2 | PDF Full-text (931 KB) | HTML Full-text | XML Full-text
Abstract
Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which controls transcription elongation of RNA polymerase II and Tat transactivation of human immunodeficiency virus. Besides P-TEFb, several proteins have been identified as HEXIM1 [...] Read more.
Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which controls transcription elongation of RNA polymerase II and Tat transactivation of human immunodeficiency virus. Besides P-TEFb, several proteins have been identified as HEXIM1 binding proteins. It is noteworthy that more than half of the HEXIM1 binding partners are involved in cancers. P53 and two key regulators of the p53 pathway, nucleophosmin (NPM) and human double minute-2 protein (HDM2), are among the factors identified. This review will focus on the functional importance of the interactions between HEXIM1 and p53/NPM/HDM2. NPM and the cytoplasmic mutant of NPM, NPMc+, were found to regulate P-TEFb activity and RNA polymerase II transcription through the interaction with HEXIM1. Importantly, more than one-third of acute myeloid leukemia (AML) patients carry NPMc+, suggesting the involvement of HEXIM1 in tumorigenesis of AML. HDM2 was found to ubiquitinate HEXIM1. The HDM2-mediated ubiquitination of HEXIM1 did not lead to protein degradation of HEXIM1 but enhanced its inhibitory activity on P-TEFb. Recently, HEXIM1 was identified as a novel positive regulator of p53. HEXIM1 prevented p53 ubiquitination by competing with HDM2 in binding to p53. Taken together, the new evidence suggests a role of HEXIM1 in regulating the p53 pathway and tumorigenesis. Full article
(This article belongs to the Special Issue The p53 Pathway in Cancers)

Journal Contact

MDPI AG
Cancers Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
cancers@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Cancers
Back to Top