Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis.

Background: The p53 isoform Δ133p53β is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored.

Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage.

Our previous studies have shown that p53 isoform expression is altered in breast cancer and related to prognosis. In particular, a high ∆40p53:p53α ratio is associated with worse disease-free survival. In this manuscript, the influence of altered Δ40p53 and p53α levels on the response to standard of care DNA-damaging agents used in breast cancer treatment was investigated in vitro.

Adaptive homeostasis and the p53 isoform network.

All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis.

Effect of p53 and its N-terminally truncated isoform, Δ40p53, on breast cancer migration and invasion.

Breast cancer is the most diagnosed malignancy in women, with over half a million women dying from this disease each year. In our previous studies, ∆40p53, an N-terminally truncated p53 isoform, was found to be upregulated in breast cancers, and a high ∆40p53 : p53α ratio was linked with worse disease-free survival. Although p53α inhibits cancer migration and invasion, little is known about the role of ∆40p53 in regulating these metastasis-related processes and its role in contributing to worse prognosis.

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

The 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 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth reference transcript encoding ∆40p53α.

Silencing of Testin expression is a frequent event in spontaneous lymphomas from Trp53-mutant mice.

The tumour suppressor gene, TES, is frequently methylated in many human tumours. Previously, we demonstrated that TES promoter methylation and transcriptional silencing was the most common molecular abnormality detected in childhood acute lymphoblastic leukaemia (ALL). Trp53-mutant mouse models predominantly develop B- and T-cell lymphomas, which are widely considered equivalent to childhood T and B ALL.

Intronic Polymorphisms Are Associated with Increased Transcript, Immune Infiltration and Cancer Risk.

We investigated the influence of selected SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.

Accessing a New Dimension in TP53 Biology: Multiplex Long Amplicon Digital PCR to Specifically Detect and Quantitate Individual Transcripts.

, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of alternative RNA splice forms and their use as clinical biomarkers has been hampered by limited specificity and quantitative accuracy of current methods.

Dephosphorylation of YB-1 is Required for Nuclear Localisation During G Phase of the Cell Cycle.

Elevated levels of nuclear Y-box binding protein 1 (YB-1) are linked to poor prognosis in cancer. It has been proposed that entry into the nucleus requires specific proteasomal cleavage. However, evidence for cleavage is contradictory and high YB-1 levels are prognostic regardless of cellular location.

The Δ133p53β isoform promotes an immunosuppressive environment leading to aggressive prostate cancer.

Prostate cancer is the second most common cancer in men, for which there are no reliable biomarkers or targeted therapies. Here we demonstrate that elevated levels of Δ133TP53β isoform characterize prostate cancers with immune cell infiltration, particularly T cells and CD163+ macrophages. These cancers are associated with shorter progression-free survival, Gleason scores ≥ 7, and an immunosuppressive environment defined by a higher proportion of PD-1, PD-L1 and colony-stimulating factor 1 receptor (CSF1R) positive cells.

Regulation of the interferon-gamma (IFN-γ) pathway by p63 and Δ133p53 isoform in different breast cancer subtypes.

The family consists of three sets of transcription factor genes, , and , each of which expresses multiple RNA variants and protein isoforms. Of these, is mutated in 25-30% of breast cancers. How mutations affect the interaction of family members and their isoforms in breast cancer is unknown.

A mouse model of the Δ133p53 isoform: roles in cancer progression and inflammation.

This review paper outlines studies on the Δ122p53 mouse, a model of the human Δ133p53 isoform, together with studies in other model organisms, cell culture, and where available, clinical investigations. In general, these studies imply that, in contrast to the canonical p53 tumor suppressor, Δ133p53 family members have oncogenic capability. Δ122p53 is multi-functional, conferring survival and proliferative advantages on cells, promoting invasion, metastasis and vascularization, as does Δ133p53.

Elevation of the TP53 isoform Δ133p53β in glioblastomas: an alternative to mutant p53 in promoting tumor development.

As tumor protein 53 (p53) isoforms have tumor-promoting, migration, and inflammatory properties, this study investigated whether p53 isoforms contributed to glioblastoma progression. The expression levels of full-length TP53α (TAp53α) and six TP53 isoforms were quantitated by RT-qPCR in 89 glioblastomas and correlated with TP53 mutation status, tumor-associated macrophage content, and various immune cell markers. Elevated levels of Δ133p53β mRNA characterised glioblastomas with increased CD163-positive macrophages and wild-type TP53.

∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling.

∆122p53 mice (a model of ∆133p53 isoform) are tumour-prone, have extensive inflammation and elevated serum IL-6. To investigate the role of IL-6 we crossed ∆122p53 mice with IL-6 null mice. Here we show that loss of IL-6 reduced JAK-STAT signalling, tumour incidence and metastasis.

Tumor protein 53 mutations are enriched in diffuse large B-cell lymphoma with irregular CD19 marker expression.

Accumulating evidence suggests tumor protein 53 (p53) promotes correct cellular differentiation. Thus, mutant TP53 may be more frequent in tumors with irregular differentiation. This study investigated whether TP53 mutations were more frequent in diffuse large B cell lymphoma (DLBCL) that lacked the B cell lineage marker CD19.

Antitumor cytotoxicity induced by bone-marrow-derived antigen-presenting cells is facilitated by the tumor suppressor protein p53 via regulation of IL-12.

Activated antigen-presenting cells (APC) deliver the three signals cytotoxic T cells require to differentiate into effector cells that destroy the tumor. These comprise antigen, co-stimulatory signals and cytokines. Once these cells have carried out their function, they apoptose.

A novel EGR-1 dependent mechanism for YB-1 modulation of paclitaxel response in a triple negative breast cancer cell line.

Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required.

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells.

Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes.

Telomere length and periodontal attachment loss: a prospective cohort study.

Aim: The aim of the study was to examine the association between telomere erosion and periodontitis in a long-standing prospective cohort study of New Zealand adults. Specific hypotheses tested were as follows: (i) that exposure to periodontitis at ages 26 and 38 was associated with accelerated leucocyte telomere erosion and (ii) that accelerated leucocyte telomere erosion was associated with higher rates of periodontitis by ages 26 and 38.

Materials And Methods: Periodontal attachment loss data were collected at ages 26 and 38.

Alpha-enolase is upregulated on the cell surface and responds to plasminogen activation in mice expressing a ∆133p53α mimic.

The p53 protein is a master regulator of the stress response. It acts as a tumor suppressor by inducing transcriptional activation of p53 target genes, with roles in apoptosis, cell cycle arrest and metabolism. The discovery of at least 12 isoforms of p53, some of which have tumor-promoting properties, has opened new avenues of research.

Increased paired box transcription factor 8 has a survival function in glioma.

Background: The molecular basis to overcome therapeutic resistance to treat glioblastoma remains unclear. The anti-apoptotic b cell lymphoma 2 (BCL2) gene is associated with treatment resistance, and is transactivated by the paired box transcription factor 8 (PAX8). In earlier studies, we demonstrated that increased PAX8 expression in glioma cell lines was associated with the expression of telomerase.

The mesenchymal architecture of the cranial mesoderm of mouse embryos is disrupted by the loss of Twist1 function.

The basic helix-loop-helix transcription factor Twist1 is a key regulator of craniofacial development. Twist1-null mouse embryos exhibit failure of cephalic neural tube closure and abnormal head development and die at E11.0.

YB-1: oncoprotein, prognostic marker and therapeutic target?

Hanahan and Weinberg have proposed the 'hallmarks of cancer' to cover the biological changes required for the development and persistence of tumours [Hanahan and Weinberg (2011) Cell 144, 646-674]. We have noted that many of these cancer hallmarks are facilitated by the multifunctional protein YB-1 (Y-box-binding protein 1). In the present review we evaluate the literature and show how YB-1 modulates/regulates cellular signalling pathways within each of these hallmarks.

Enhanced isolation of fibroblasts from human skin explants.

Here we describe a method for growing fibroblasts from human skin explants that increases the number of cells obtained by up to two orders of magnitude, thus increasing the amount of material available for research and diagnostic purposes and potentially for cell-based therapies. Explants can be transferred sequentially up to 80 times, if required, at which point the explants appear to be completely depleted of fibroblasts. Utilizing skin samples obtained from 16 donors, aged 18-66 years old, the first 20 transfers produced cultures with lifespan and growth characteristics that were all very similar to each other, but the cultures derived from later transfers had a decreasing replicative capacity.

Does Δ133p53 isoform trigger inflammation and autoimmunity?

Autoimmune diseases are characterized by the immune system mounting a response against self. The exact etiology of autoimmune diseases and autoimmunity remain unclear. Here, we demonstrate that Δ133p53, an isoform of the tumor suppressor protein p53, is involved in the development of autoimmunity.