p53 shades of Hippo

Abstract

The three p53 family members, p53, p63 and p73, are structurally similar and share many biochemical activities. Yet, along with their common fundamental role in protecting genomic fidelity, each has acquired distinct functions related to diverse cell autonomous and non-autonomous processes. Similar to the p53 family, the Hippo signaling pathway impacts a multitude of cellular processes, spanning from cell cycle and metabolism to development and tumor suppression. The core Hippo module consists of the tumor-suppressive MST-LATS kinases and oncogenic transcriptional co-effectors YAP and TAZ. A wealth of accumulated data suggests a complex and delicate regulatory network connecting the p53 and Hippo pathways, in a highly context-specific manner. This generates multiple layers of interaction, ranging from interdependent and collaborative signaling to apparent antagonistic activity. Furthermore, genetic and epigenetic alterations can disrupt this homeostatic network, paving the way to genomic instability and cancer. This strengthens the need to better understand the nuances that control the molecular function of each component and the cross-talk between the different components. Here, we review interactions between the p53 and Hippo pathways within a subset of physiological contexts, focusing on normal stem cells and development, as well as regulation of apoptosis, senescence and metabolism in transformed cells.

The Pemphigus Vulgaris antigen desmoglein-3 suppresses p53 function via the YAP-Hippo pathway

“…However, this mechanism has not been thoroughly investigated in human keratinocytes. Given that, 1) the biological functions of p53 and the Hippo pathway overlap at multiple levels and their upstream cues remain largely unknown (Furth et al, 2018); 2) the Hippo pathway is required in E-cadherin mediated contact inhibition of proliferation (CIP) in dense cell populations (Kim et al, 2011) and as we and others have shown that Dsg3 engages in cross talk with E-cadherin and regulates its adhesive function (Rotzer et al, 2015;Tsang et al, 2010;Tsang et al, 2012b), we decided to analyse the Hippo pathway and its downstream effector, YAP (Furth et al, 2018). First, we analysed, by Western blotting, the expression of YAP, as well as pYAP-S127 (an indicator of the Hippo pathway (Piccolo et al, 2014)), alongside p53 in confluent NTERT cells with and without Dsg3 knockdown and subjected the cells to equiaxial cyclic strain (the experiment as described above).…”

Reviewing the future of the P53 field

“…Activation of p53-mediated transcription by various stress signals results in the expression of a number of pathways that accomplish diverse phenotypes that include cell cycle arrest, 3 senescence, apoptosis and other types of cell death, metabolic alterations, DNA repair processes, and other prosurvival mechanisms and tumor suppression (reviewed in refs. [3][4][5][6][7]. There is an active debate about which p53-regulated genes and pathways are responsible for the tumor suppressor phenotype.…”

“…5,6 The answer to this question may reside in a better understanding of how stress activates the p53 protein and how a particular stress initiates a transcriptional pathway resulting in an improved fidelity in the process of cellular replication. 7 P53-regulated gene products interact with many other signal transduction pathways involved in metabolism and growth (PI3K-mTOR pathways), stem cells (the Wnt pathway), and development affecting the p53-Hippo pathways, 7 the immune system, the fidelity of epigenetic signals, senescence, aging and life span, or death (reviewed in Wu and Prives 8 ). It appears that p53-mediated functions are involved from early development, through life, and in death.…”

“…In vertebrates, this family of transcription factors has a critical role in protecting the host skin's protective barrier, inducing the innate immune response, preventing movement of retrotransposons in the genome and genomic instability, hypoxia, mitochondrial functions, regulating metabolic pathways and glucose and glutamine utilization, regulating the rates of cell division, maintaining epigenetic stability, monitoring centrosome fidelity and chromosomal segregation (aneuploidy), monitoring and inhibiting viral and bacterial infections, and many other responses to our environment. [3][4][5][6][7]9 Hidden in some of these functions are the processes of aging and death. 8 From germ line development, through fertilization, embryonic development, epigenetic programing, birth, organismic development, reproduction, aging, and death, the Tp53 family of genes, first observed over a billion years ago, has an important role throughout our lives by providing fidelity in spite of stress.…”

Exercício físico aeróbico de intensidade moderada reduz a velocidade de crescimento e modula o metabolismo energético tumoral em modelo experimental de câncer de mama triplo-negativo

“…Além disso, a via Hippo também está relacionada às metástases ósseas do câncer de mama pela ativação de YAP/TAZ em células tumorais (Rashidian et al, 2015;Li et al, 2017). Várias linhas de evidência sugerem que a deleção ou mutação de LATS1/2 leva a um fenótipo de câncer de mama mais agressivo, com maior capacidade invasiva (Visser e Yang, 2010;Maugeri-Sacca e De Maria, 2016;Li et al, 2017;Furth et al, 2018;Wei et al, 2018) e evidências têm sugerido que um dos pontos importantes para a ativação da via Hippo são perturbações homeostáticas relacionadas à privação de substratos energéticos (Mao et al, 2015;Ardestani et al, 2018;Furth et al, 2018).…”