Distinct interactors define the p63 transcriptional signature in epithelial development or cancer.

The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3'-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.

NH-sulfoximine: A novel pharmacological inhibitor of the mitochondrial F1 Fo -ATPase, which suppresses viability of cancerous cells.

BACKGROUND AND PURPOSE: The mitochondrial F1 Fo -ATPsynthase is pivotal for cellular homeostasis. When respiration is perturbed, its mode of action everts becoming an F1 Fo -ATPase and therefore consuming rather producing ATP. Such a reversion is an obvious target for pharmacological intervention to counteract pathologies. Despite this, tools to selectively inhibit the phases of ATP hydrolysis without affecting the production of ATP remain scarce. Here, we report on a newly synthesised chemical, the NH-sulfoximine (NHS), which achieves such a selectivity. EXPERIMENTAL APPROACH: The chemical structure of the F1 Fo -ATPase inhibitor BTB-06584 was used as a template to synthesise NHS. We assessed its pharmacology in human neuroblastoma SH-SY5Y cells in which we profiled ATP levels, redox signalling, autophagy pathways and cellular viability. NHS was given alone or in combination with either the glucose analogue 2-deoxyglucose (2-DG) or the chemotherapeutic agent etoposide. KEY RESULTS: NHS selectively blocks the consumption of ATP by mitochondria leading a subtle cytotoxicity associated via the concomitant engagement of autophagy which impairs cell viability. NHS achieves such a function independently of the F1 Fo -ATPase inhibitory factor 1 (IF1). CONCLUSION AND IMPLICATIONS: The novel sulfoximine analogue of BTB-06584, NHS, acts as a selective pharmacological inhibitor of the mitochondrial F1 Fo -ATPase. NHS, by blocking the hydrolysis of ATP perturbs the bioenergetic homoeostasis of cancer cells, leading to a non-apoptotic type of cell death.