Δ133p53β isoform pro-invasive activity is regulated through an aggregation-dependent mechanism in cancer cells

The p53 isoform, Δ133p53β, is critical in promoting cancer. Here we report that Δ133p53β activity is regulated through an aggregation-dependent mechanism. Δ133p53β aggregates were observed in cancer cells and tumour biopsies. The Δ133p53β aggregation depends on association with interacting partners including p63 family members or the CCT chaperone complex. Depletion of the CCT complex promotes accumulation of Δ133p53β aggregates and loss of Δ133p53β dependent cancer cell invasion. In contrast, association with p63 family members recruits Δ133p53β from aggregates increasing its intracellular mobility. Our study reveals novel mechanisms of cancer progression for p53 isoforms which are regulated through sequestration in aggregates and recruitment upon association with specific partners like p63 isoforms or CCT chaperone complex, that critically influence cancer cell features like EMT, migration and invasion.

Tissue-specific expression of p73 and p63 isoforms in human tissues

Abstractp73 and p63 are members of the p53 family that exhibit overlapping and distinct functions in development and homeostasis. The evaluation of p73 and p63 isoform expression across human tissue can provide greater insight to the functional interactions between family members. We determined the mRNA isoform expression patterns of TP73 and TP63 across a panel of 36 human tissues and protein expression within the highest-expressing tissues. TP73 and TP63 expression significantly correlated across tissues. In tissues with concurrent mRNA expression, nuclear co-expression of both proteins was observed in a majority of cells. Using GTEx data, we quantified p73 and p63 isoform expression in human tissue and identified that the α-isoforms of TP73 and TP63 were the predominant isoform expressed in nearly all tissues. Further, we identified a previously unreported p73 mRNA product encoded by exons 4 to 14. In sum, these data provide the most comprehensive tissue-specific atlas of p73 and p63 protein and mRNA expression patterns in human and murine samples, indicating coordinate expression of these transcription factors in the majority of tissues in which they are expressed.

Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and ΔNp63 ubiquitination and degradation

The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.

p63-related signaling at a glance

ABSTRACTp63 (also known as TP63) is a transcription factor of the p53 family, along with p73. Multiple isoforms of p63 have been discovered and these have diverse functions encompassing a wide array of cell biology. p63 isoforms are implicated in lineage specification, proliferative potential, differentiation, cell death and survival, DNA damage response and metabolism. Furthermore, p63 is linked to human disease states including cancer. p63 is critical to many aspects of cell signaling, and in this Cell science at a glance article and the accompanying poster, we focus on the signaling cascades regulating TAp63 and ΔNp63 isoforms and those that are regulated by TAp63 and ΔNp63, as well the role of p63 in disease.

Overexpression of p63 Protein in Patients with Seborrheic Keratosis in the Setting of Carbohydrate Metabolism Disorders

Aim. The paper studies p63 expression in patients with seborrheic keratosis in the presence or absence of carbohydrate metabolism disorders.Materials and methods. The study involved 130 patients with seborrheic keratosis. Following the endocrinologist’s consultation, the patients were divided into two groups. The fi rst group comprised 68 people: 44 patients with type 2 diabetes and 24 patients with impaired glucose tolerance. The second group was composed of patients without carbohydrate metabolism disorders (62 people). The authors performed a histological study and an immunohistochemical (IHC) test using monoclonal antibodies to р63. The results of the IHC test were analysed according to the number of stained tumour cells: 0 — no response or weak staining of less than 10% of the cells, 1 — from 10% to 30% of tumour cells are stained, 2 — staining of more than 30% of tumor cells; as well as according to the colour intensity: weak (+) and marked (++).Results. The IHC test using monoclonal antibodies to р63 produced a positive reaction in 82.3% of cases. Sixty-fi ve seborrheic keratomas (SK) (50%) exhibited a diffuse pronounced expression of p63. Weak nuclear staining (10%–30% of cells) was recorded in 42 SKs (32.3%). The study revealed a high correlation dependence of p63 expression in SK on the presence of carbohydrate metabolism disorders in patients (R = 0.82, p = 0.0000001). Thus, in patients with carbohydrate metabolism disorders, overexpression of p63 in SKs was found to be signifi cantly higher — 89.7%, as compared to 6.4% in patients without impaired carbohydrate metabolism (p = 0.00001).Conclusion. P63 overexpression in seborrheic keratosis correlates with the presence of chronic hyperglycemia in patients. Disruption of cellular metabolism leads to changes in the balance between p63 isoforms and plays an important role in the pathogenesis of seborrheic keratosis.