The Δ133p53 Isoforms, Tuners of the p53 Pathway

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.

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Targeting cellular senescence in cancer and aging: roles of p53 and its isoforms

Carcinogenesis ◽

10.1093/carcin/bgaa071 ◽

2020 ◽

Vol 41 (8) ◽

pp. 1017-1029 ◽

Cited By ~ 2

Author(s):

Jessica Beck ◽

Casmir Turnquist ◽

Izumi Horikawa ◽

Curtis Harris

Keyword(s):

Cellular Senescence ◽

Therapeutic Potential ◽

P53 Protein ◽

Tp53 Gene ◽

Suppressor Gene ◽

Cellular Reprogramming ◽

Protein Isoforms ◽

Age Related ◽

Alternative Mrna Splicing ◽

P53 Isoforms

Abstract Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.

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Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness

Molecules ◽

10.3390/molecules26123737 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3737

Author(s):

Joana Moreira ◽

Joana Almeida ◽

Lucília Saraiva ◽

Honorina Cidade ◽

Madalena Pinto

Keyword(s):

Antitumor Agents ◽

P53 Protein ◽

Cancer Therapeutics ◽

Tp53 Gene ◽

Inhibitory Effect ◽

Pharmacokinetic Parameters ◽

P53 Pathway ◽

Protein Inhibition ◽

In Silico Studies ◽

Binding Cleft

The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53–MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53–MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.

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Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript Expression: Insights from TP53 Long Amplicon Digital PCR Assays

Cancers ◽

10.3390/cancers13071531 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1531

Author(s):

Annette Lasham ◽

Nicholas Knowlton ◽

Sunali Y. Mehta ◽

Antony W. Braithwaite ◽

Cristin G. Print

Keyword(s):

Breast Cancer ◽

Gene Locus ◽

Tp53 Mutation ◽

P53 Protein ◽

Tp53 Gene ◽

Digital Pcr ◽

Protein Isoforms ◽

Alternative Transcript ◽

Transcript Expression ◽

Splice Sites

The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth TP53 reference transcript encoding ∆40p53α. We then applied these assays, alongside DNA sequencing of the TP53 gene locus, to tumors from a cohort of New Zealand (NZ) breast cancer patients. We found a high prevalence of mutations at TP53 splice sites in the NZ breast cancer cohort. Mutations at TP53 intron 4 splice sites were associated with overexpression of ∆133TP53 transcripts. Cox proportional hazards survival analysis showed that interplay between TP53 mutation status and expression of TP53 transcript variants was significantly associated with patient outcome, over and above standard clinical and pathological information. In particular, patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1, which derive from alternative intron 1 acceptor splice sites, had a remarkably good outcome. We suggest that this type of analysis, integrating mutation and transcript expression, provides a step-change in our understanding of TP53 in cancer.

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Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1205664109 ◽

2012 ◽

Vol 109 (38) ◽

pp. E2543-E2550 ◽

Cited By ~ 45

Author(s):

Jinxiong Wei ◽

Jennifer Noto ◽

Elena Zaika ◽

Judith Romero-Gallo ◽

Pelayo Correa ◽

...

Keyword(s):

Helicobacter Pylori ◽

Expression Profile ◽

P53 Protein ◽

Pathogenic Bacterium ◽

Protein Isoforms ◽

Cellular Damage ◽

Mongolian Gerbils ◽

Cellular Stresses ◽

H Pylori ◽

P53 Isoforms

The p53 protein plays a central role in the prevention of tumorigenesis. Cellular stresses, such as DNA damage and aberrant oncogene activation, trigger induction of p53 that halts cellular proliferation and allows cells to be repaired. If cellular damage is beyond the capability of the repair mechanisms, p53 induces apoptosis or cell cycle arrest, preventing damaged cells from becoming cancerous. However, emerging evidence suggests that the function of p53 needs to be considered as isoform-specific. Here, we report that the expression profile of p53 can be shifted toward inhibitory p53 isoforms by the pathogenic bacterium Helicobacter pylori, which is known for its strong association with gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. We found that interaction of H. pylori with gastric epithelial cells, mediated via the cag pathogenicity island, induces N-terminally truncated ∆133p53 and ∆160p53 isoforms in human cells. Induction of an orthologous p53 isoform, ∆153p53, was also found in H. pylori-infected Mongolian gerbils. The p53 isoforms inhibit p53 and p73 activities, induce NF-κB, and increase survival of infected cells. Expression of ∆133p53, in response to H. pylori infection, is regulated by phosphorylation of c-Jun and activation of activator protein-1–dependent transcription. Together, these results provide unique insights into the regulation of p53 protein and may contribute to the understanding of tumorigenesis associated with H. pylori.

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The Mysteries around the BCL-2 Family Member BOK

Biomolecules ◽

10.3390/biom10121638 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1638

Author(s):

Raed Shalaby ◽

Hector Flores-Romero ◽

Ana J. García-Sáez

Keyword(s):

Family Member ◽

Cell Fate ◽

Current Knowledge ◽

Structural Features ◽

Special Focus ◽

Cellular Functions ◽

Open Questions ◽

Apoptotic Protein ◽

Evolutionarily Conserved ◽

Apoptosis Regulation

BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions.

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Recent Synthetic Approaches towards Small Molecule Reactivators of p53

Biomolecules ◽

10.3390/biom10040635 ◽

2020 ◽

Vol 10 (4) ◽

pp. 635 ◽

Cited By ~ 1

Author(s):

Jerson L. Silva ◽

Carolina G. S. Lima ◽

Luciana P. Rangel ◽

Giulia D. S. Ferretti ◽

Fernanda P. Pauli ◽

...

Keyword(s):

Tumor Suppressor ◽

Small Molecules ◽

P53 Protein ◽

Tp53 Gene ◽

Therapy Resistance ◽

Main Function ◽

Tumor Suppressor Function ◽

Cellular Functions ◽

Synthetic Approaches ◽

Integrity Of Dna

The tumor suppressor protein p53 is often called “the genome guardian” and controls the cell cycle and the integrity of DNA, as well as other important cellular functions. Its main function is to trigger the process of apoptosis in tumor cells, and approximately 50% of all cancers are related to the inactivation of the p53 protein through mutations in the TP53 gene. Due to the association of mutant p53 with cancer therapy resistance, different forms of restoration of p53 have been subject of intense research in recent years. In this sense, this review focus on the main currently adopted approaches for activation and reactivation of p53 tumor suppressor function, focusing on the synthetic approaches that are involved in the development and preparation of such small molecules.

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Translation of human Δ133p53 mRNA and its targeting by antisense oligonucleotides complementary to the 5′-terminal region of this mRNA

PLoS ONE ◽

10.1371/journal.pone.0256938 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0256938

Author(s):

Paulina Żydowicz-Machtel ◽

Mariola Dutkiewicz ◽

Agata Swiatkowska ◽

Dorota Gurda-Woźna ◽

Jerzy Ciesiołka

Keyword(s):

Secondary Structure ◽

Antisense Oligonucleotides ◽

Transcription Initiation ◽

P53 Protein ◽

Initiation Site ◽

Terminal Region ◽

Protein Isoforms ◽

P53 Isoforms ◽

P53 Mrna

The p53 protein is expressed as at least twelve protein isoforms. Within intron 4 of the human TP53 gene, a P2 transcription initiation site is located and this transcript encodes two p53 isoforms: Δ133p53 and Δ160p53. Here, the secondary structure of the 5′-terminal region of P2-initiated mRNA was characterized by means of the SHAPE and Pb2+-induced cleavage methods and for the first time, a secondary structure model of this region was proposed. Surprisingly, only Δ133p53 isoform was synthetized in vitro from the P2-initiated p53 mRNA while translation from both initiation codons occurred after the transfection of vector-encoded model mRNA to HCT116 cells. Interestingly, translation performed in the presence of the cap analogue suggested that the cap-independent process contributes to the translation of P2-initiated p53 mRNA. Subsequently, several antisense oligonucleotides targeting the 5′-terminal region of P2-initiated p53 mRNA were designed. The selected oligomers were applied in in vitro translation assays as well as in cell lines and their impact on the Δ133p53 synthesis and on cell viability was investigated. The results show that these oligomers are attractive tools in the modulation of the translation of P2-initiated p53 mRNA through attacking the 5′ terminus of the transcript. Since cell proliferation is also reduced by antisense oligomers that lower the level of Δ133p53, this demonstrates an involvement of this isoform in tumorigenesis.

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Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

Endocrine Related Cancer ◽

10.1530/erc-17-0139 ◽

2017 ◽

Vol 24 (10) ◽

pp. R349-R366 ◽

Cited By ~ 19

Author(s):

Catherine Zabkiewicz ◽

Jeyna Resaul ◽

Rachel Hargest ◽

Wen Guo Jiang ◽

Lin Ye

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Bone Morphogenetic Proteins ◽

Therapeutic Potential ◽

Current Knowledge ◽

Breast Tumour ◽

Cellular Functions ◽

Foetal Development ◽

Key Factor ◽

The Right

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis.

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Modulating Tumor Cell Functions by Tunable Nanopatterned Ligand Presentation

Nanomaterials ◽

10.3390/nano10020212 ◽

2020 ◽

Vol 10 (2) ◽

pp. 212

Author(s):

Katharina Amschler ◽

Michael P. Schön

Keyword(s):

Extracellular Matrix ◽

Tumor Cell ◽

Cell Fate ◽

Epithelial Mesenchymal Transition ◽

Model Systems ◽

Cellular Functions ◽

Biophysical Parameters ◽

Ligand Density ◽

Mesenchymal Transition ◽

Cell Functions

Cancer comprises a large group of complex diseases which arise from the misrouted interplay of mutated cells with other cells and the extracellular matrix. The extracellular matrix is a highly dynamic structure providing biochemical and biophysical cues that regulate tumor cell behavior. While the relevance of biochemical signals has been appreciated, the complex input of biophysical properties like the variation of ligand density and distribution is a relatively new field in cancer research. Nanotechnology has become a very promising tool to mimic the physiological dimension of biophysical signals and their positive (i.e., growth-promoting) and negative (i.e., anti-tumoral or cytotoxic) effects on cellular functions. Here, we review tumor-associated cellular functions such as proliferation, epithelial-mesenchymal transition (EMT), invasion, and phenotype switch that are regulated by biophysical parameters such as ligand density or substrate elasticity. We also address the question of how such factors exert inhibitory or even toxic effects upon tumor cells. We describe three principles of nanostructured model systems based on block copolymer nanolithography, electron beam lithography, and DNA origami that have contributed to our understanding of how biophysical signals direct cancer cell fate.

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Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

Science Signaling ◽

10.1126/scisignal.abd8379 ◽

2020 ◽

Vol 13 (663) ◽

pp. eabd8379

Author(s):

Heba Ali ◽

Lena Marth ◽

Dilja Krueger-Burg

Keyword(s):

Synaptic Transmission ◽

Synapse Formation ◽

Current Knowledge ◽

Protein Complexes ◽

Inhibitory Synapses ◽

Molecular Architecture ◽

Cellular Functions ◽

Altered Expression ◽

Health And Disease ◽

Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

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