Cell surface G protein–coupled receptors (GPCRs), upon agonist binding, undergo serine–threonine phosphorylation, leading to either receptor recycling or degradation. Here, we show a new fate of GPCRs, exemplified by ER retention of sphingosine-1-phosphate receptor 1 (S1PR1). We show that S1P phosphorylates S1PR1 on tyrosine residue Y143, which is associated with recruitment of activated BiP from the ER into the cytosol. BiP then interacts with endocytosed Y143-S1PR1 and delivers it into the ER. In contrast to WT-S1PR1, which is recycled and stabilizes the endothelial barrier, phosphomimicking S1PR1 (Y143D-S1PR1) is retained by BiP in the ER and increases cytosolic Ca2+ and disrupts barrier function. Intriguingly, a proinflammatory, but non-GPCR agonist, TNF-α, also triggered barrier-disruptive signaling by promoting S1PR1 phosphorylation on Y143 and its import into ER via BiP. BiP depletion restored Y143D-S1PR1 expression on the endothelial cell surface and rescued canonical receptor functions. Findings identify Y143-phosphorylated S1PR1 as a potential target for prevention of endothelial barrier breakdown under inflammatory conditions.

P53, a homo-tetrameric protein found in mammalian cells, derives its name from the fact that it settles at around 53KDa position in SDS-PAGE, due to a “kink” in its structure. In its functional state, p53 forms a homo-tetramer and binds to the promoters of a wide array of genes. Binding of p53 downregulates the transcription of target genes. Most of the gene targets of p53 are involved in cell cycle progression, and therefore, any malfunctions associated with p53 have catastrophic consequences for the cell. The gene encoding for p53 known as TP53 is the most well-studied gene in the entire genome because of being the most highly mutated gene in all cancer types. It is due to this widely accepted and documented “cell protective feature” that p53 is generally referred to as “the guardian of the genome.” In this chapter, we will discuss the involvement of p53 in relation to carcinogenesis. We will also cover the major functions of p53 under normal conditions, major mutations of the TP53 gene, and their association with different forms of cancer.

Epigenetics “above or over genetics” is the term used for processes that result in modifications which are stably inherited through cell generations, without changing the underlying DNA sequence of the cell. These include DNA methylation, Post-translational histone modification and non-coding RNAs. Over the last two decades, interest in the field of epigenetics has grown manifold because of the realization of its involvement in key cellular and pathological processes beyond what was initially anticipated. Epigenetics and chromatin biology have been underscored to play key roles in diseases like cancer. The landscape of different epigenetic signatures can vary considerably from one cancer type to another, and even from one ethnic group to another in the case of same cancer. This chapter discusses the emerging role of epigenetics and chromatin biology in the field of cancer research. It discusses about the different forms of epigenetic mechanisms and their respective role in carcinogenesis in the light of emerging research.

Aberrant polymorphonuclear neutrophil (PMN) accumulation in tissues induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and “do not eat me” signals due to impaired synthesis of the deubiquitinase A20. Decreased A20 levels, in turn, activated the transcription factor NF-κB and the secretion of MIP2α (human homolog of IL-8) in ECs. EC-secreted MIP2α/IL-8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in ECs or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg ^–/– mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC/Erg/A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.