Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

p53 Isoforms and Their Functions in Cancer Studies

Special Issue Editors
Special Issue Information
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 August 2023) | Viewed by 7514

Share This Special Issue

Special Issue Editor

Dr. Gilles Gadea

E-Mail Website
Guest Editor

Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier, INSERM U1194, IRCM, F-34298 Montpellier, France
Interests: cancer biology; mdm2; liposarcomas; metabolism; extracellular vesicles; p53 isoforms

Special Issue Information

Dear Colleagues,

The p53 protein was first discovered in 1979, and characterized as an oncogene until it was later found to be a mutated form. Many publications later (more than 112.000 indexed in Pubmed), p53 is now well established as “the guardian of the genome”, which is critical for preserving genome integrity. However, p53 activity plays other roles aside from keeping the genome safe; over the years, it has been attributed functions in all cancer hallmarks. This is only possible because of the large gene cooperation and protein interactions developed by p53. Although a plethora of information has already been accumulated on p53, a tremendous amount of work is still needed to uncover the entire complexity of the p53 protein and its critical role in tumor genesis and progression. Understanding the genetic and epigenetic mechanisms that control the p53 protein, as well as its complex post-translational regulation, will hopefully help with the design of more effective therapies against p53 in cancer.

This IJMS Special Issue, “p53 Isoforms and Their Functions in Cancer Studies”, will focus on original studies describing the unraveled roles of p53 isoforms. Studies exploring their clinical relevance in the diagnosis and effective treatments of cancer are of particular interest.

Dr. Gilles Gadea
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (3 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

16 pages, 2902 KiB

Open AccessArticle

p53 Dysregulation in Breast Cancer: Insights on Mutations in the TP53 Network and p53 Isoform Expression

by Luiza Steffens Reinhardt, Kira Groen, Alexandre Xavier and Kelly A. Avery-Kiejda

Int. J. Mol. Sci. 2023, 24(12), 10078; https://doi.org/10.3390/ijms241210078 - 13 Jun 2023

Cited by 2 | Viewed by 2320

Abstract

In breast cancer, p53 expression levels are better predictors of outcome and chemotherapy response than TP53 mutation. Several molecular mechanisms that modulate p53 levels and functions, including p53 isoform expression, have been described, and may contribute to deregulated p53 activities and worse cancer outcomes. In this study, TP53 and regulators of the p53 pathway were sequenced by targeted next-generation sequencing in a cohort of 137 invasive ductal carcinomas and associations between the identified sequence variants, and p53 and p53 isoform expression were explored. The results demonstrate significant variability in levels of p53 isoform expression and TP53 variant types among tumours. We have shown that TP53 truncating and missense mutations modulate p53 levels. Further, intronic mutations, particularly polymorphisms in intron 4, which can affect the translation from the internal TP53 promoter, were associated with increased Δ133p53 levels. Differential expression of p53 and p53 isoforms was associated with the enrichment of sequence variants in p53 interactors BRCA1, PALB2, and CHEK2. Taken together, these results underpin the complexity of p53 and p53 isoform regulation. Furthermore, given the growing evidence associating dysregulated levels of p53 isoforms with cancer progression, certain TP53 sequence variants that show strong links to p53 isoform expression may advance the field of prognostic biomarker study in breast cancer. Full article

(This article belongs to the Special Issue p53 Isoforms and Their Functions in Cancer Studies)

► Show Figures

Figure 1

20 pages, 6250 KiB

Open AccessArticle

Splicing Modulation Results in Aberrant Isoforms and Protein Products of p53 Pathway Genes and the Sensitization of B Cells to Non-Genotoxic MDM2 Inhibition

by Erhan Aptullahoglu, Carmela Ciardullo, Jonathan P. Wallis, Helen Marr, Scott Marshall, Nick Bown, Elaine Willmore and John Lunec

Int. J. Mol. Sci. 2023, 24(3), 2410; https://doi.org/10.3390/ijms24032410 - 26 Jan 2023

Cited by 5 | Viewed by 1977

Abstract

Several molecular subtypes of cancer are highly dependent on splicing for cell survival. There is a general interest in the therapeutic targeting of splicing by small molecules. E7107, a first-in-class spliceosome inhibitor, showed strong growth inhibitory activities against a large variety of human cancer xenografts. Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous hematologic malignancy, with approximately 90% of cases being TP53 wild-type at diagnosis. An increasing number of studies are evaluating alternative targeted agents in CLL, including MDM2–p53 binding antagonists. In this study, we report the effect of splicing modulation on key proteins in the p53 signalling pathway, an important cell death pathway in B cells. Splicing modulation by E7107 treatment reduced full-length MDM2 production due to exon skipping, generating a consequent reciprocal p53 increase in TP53^WT cells. It was especially noteworthy that a novel p21^WAF1 isoform with compromised cyclin-dependent kinase inhibitory activity was produced due to intron retention. E7107 synergized with the MDM2 inhibitor RG7388, via dual MDM2 inhibition; by E7107 at the transcript level and by RG7388 at the protein level, producing greater p53 stabilisation and apoptosis. This study provides evidence for a synergistic MDM2 and spliceosome inhibitor combination as a novel approach to treat CLL and potentially other haematological malignancies. Full article

(This article belongs to the Special Issue p53 Isoforms and Their Functions in Cancer Studies)

► Show Figures

Figure 1

27 pages, 4174 KiB

Open AccessArticle

Polyploid/Multinucleated Giant and Slow-Cycling Cancer Cell Enrichment in Response to X-ray Irradiation of Human Glioblastoma Multiforme Cells Differing in Radioresistance and TP53/PTEN Status

by Lina Alhaddad, Roman Chuprov-Netochin, Margarita Pustovalova, Andreyan N. Osipov and Sergey Leonov

Int. J. Mol. Sci. 2023, 24(2), 1228; https://doi.org/10.3390/ijms24021228 - 8 Jan 2023

Cited by 5 | Viewed by 2496

Abstract

Radioresistance compromises the efficacy of radiotherapy for glioblastoma multiforme (GBM), the most devastating and common brain tumor. The present study investigated the relationship between radiation tolerance and formation of polyploid/multinucleated giant (PGCC/MGCC) and quiescent/senescent slow-cycling cancer cells in human U-87, LN-229, and U-251 cell lines differing in TP53/PTEN status and radioresistance. We found significant enrichment in MGCC populations of U-87 and LN-229 cell lines, and generation of numerous small mononuclear (called Raju cells, or RJ cells) U-87-derived cells that eventually form cell colonies, in a process termed neosis, in response to X-ray irradiation (IR) at single acute therapeutic doses of 2–6 Gy. For the first time, single-cell high-content imaging and analysis of Ki-67- and EdU-coupled fluorescence demonstrated that the IR exposure dose-dependently augments two distinct GBM cell populations. Bifurcation of Ki-67 staining suggests fast-cycling and slow-cycling populations with a normal-sized nuclear area, and with an enlarged nuclear area, including one resembling the size of PGCC/MGCCs, that likely underlie the highest radioresistance and propensity for repopulation of U-87 cells. Proliferative activity and anchorage-independent survival of GBM cell lines seem to be related to neosis, low level of apoptosis, fraction of prematurely stress-induced senescent MGCCs, and the expression of p63 and p73, members of p53 family transcription factors, but not to the mutant p53. Collectively, our data support the importance of the TP53wt/PTENmut genotype for the maintenance of cycling radioresistant U-87 cells to produce a significant amount of senescent MGCCs as an IR stress-induced adaptation response to therapeutic irradiation doses. Full article

(This article belongs to the Special Issue p53 Isoforms and Their Functions in Cancer Studies)

► Show Figures

Journal Menu

Journal Browser

p53 Isoforms and Their Functions in Cancer Studies

Share This Special Issue

Special Issue Editor

Special Issue Information

Published Papers (3 papers)

Research

Further Information

Guidelines

MDPI Initiatives

Follow MDPI