Metabolic regulation by p53

We are increasingly aware that cellular metabolism plays a vital role in diseases such as cancer, and that p53 is an important regulator of metabolic pathways. By transcriptional activation and other means, p53 is able to contribute to the regulation of glycolysis, oxidative phosphorylation, glutaminolysis, insulin sensitivity, nucleotide biosynthesis, mitochondrial integrity, fatty acid oxidation, antioxidant response, autophagy and mTOR signalling. The ability to positively and negatively regulate many of these pathways, combined with feedback signalling from these pathways to p53, demonstrates the reciprocal and flexible nature of the regulation, facilitating a diverse range of responses to metabolic stress. Intriguingly, metabolic stress triggers primarily an adaptive (rather than pro-apoptotic) p53 response, and p53 is emerging as an important regulator of metabolic homeostasis. A better understanding of how p53 coordinates metabolic adaptation will facilitate the identification of novel therapeutic targets and will also illuminate the wider role of p53 in human biology

ИССЛЕДОВАНИЯ БИОЛОГИЧЕСКИХ ОБЪЕКТОВ НА КЛЕТОЧНОМ И СУБКЛЕТОЧНОМ УРОВНЕ С ПОМОЩЬЮ ФЕМТОСЕКУНДНОГО ЛАЗЕРНОГО ОПТИЧЕСКОГО ПИНЦЕТА-СКАЛЬПЕЛЯ

The aim of this work was developing of elements of the precise three-dimensional positioning technology of one or several micron and submicron size biological objects. Thereto a laboratory unit of hardware-software complex of optical femtosecond laser tweezers-scalpel was developed and constructed in the Joint institute for high temperatures RAS using material resources of Russia. Experimental data concerning a maximal manipulation speed of CHO and cells, produced from mammalian spinal ganglia (using protocols for producing pure culture of Schwann cells) was received. Besides facts of interaction of laser radiation with intracellular structures that lead to unexpected behavior of cell in the zone of optical trap and change of maximal speed of cell manipulation were determined. Целью данной работы является разработка элементов технологии прецизионного трехмерного позицио- нирования одного или нескольких биологических объектов микронного и субмикронного размеров. Для этого в Объединенном институте высоких температур РАН разработан и изготовлен лабораторный обра- зец программно-аппаратного комплекса оптического фемтосекундного лазерного пинцета-скальпеля на основе приборной базы, производимой в России. Получены экспериментальные результаты о максималь- ной скорости манипулирования CHO и клетками культуры, полученной из спинального ганглия млекопи- тающего (по протоколам получения очищенных культур шванновских клеток), а также о взаимодействии излучения с внутриклеточными структурами, которое приводит к изменению предполагаемого поведе- ния клетки в области оптической ловушки и максимальной скорости манипулирования последней.

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 ‘hotspot’ mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53–p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.JE Noll, J Jeffery, F Al-Ejeh, R Kumar, KK Khanna, DF Callen and PM Neilse

CELLULAR AND SUBCELLULAR LEVEL INVESTIGATION OF BIOLOGICAL OBJECTS BY MEANS OF FEMTOSECOND LASER OPTICAL TWEEZERS-SCALPEL

The aim of this work was developing of elements of the precise three-dimensional positioning technology of one or several micron and submicron size biological objects. Thereto a laboratory unit of hardware-software complex of optical femtosecond laser tweezers-scalpel was developed and constructed in the Joint institute for high temperatures RAS using material resources of Russia. Experimental data concerning a maximal manipulation speed of CHO and cells, produced from mammalian spinal ganglia (using protocols for producing pure culture of Schwann cells) was received. Besides facts of interaction of laser radiation with intracellular structures that lead to unexpected behavior of cell in the zone of optical trap and change of maximal speed of cell manipulation were determined

Vitamin D and colon cancer

The most active vitamin D metabolite, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a pleiotropic hormone with wide regulatory actions. Classically, vitamin D deficiency was known to alter calcium and phosphate metabolism and bone biology. In addition, recent epidemiological and experimental studies support the association of vitamin D deficiency with a large variety of human diseases, and particularly with the high risk of colorectal cancer. By regulating the expression of many genes via several mechanisms, 1,25(OH)2D3 induces differentiation, controls the detoxification metabolism and cell phenotype, sensitises cells to apoptosis and inhibits the proliferation of cultured human colon carcinoma cells. Consistently, 1,25(OH)2D3 and several of its analogues decrease intestinal tumourigenesis in animal models. Molecular, genetic and clinical data in humans are scarce but they suggest that vitamin D is protective against colon cancer. Clearly, the available evidence warrants new, well-designed, large-scale trials to clarify the role of vitamin D in the prevention and/or therapy of this important neoplasia.The work in the authors’ laboratory is supported by Ministerio de Ciencia e Innovación of Spain (grant number SAF2010-18302), Fondo Europeo de Desarrollo Regional- Instituto de Salud Carlos III (grant number RD06/0020/0009) and Comunidad de Madrid (grant number S2011/BMD-2344, Colomics2).Peer Reviewe

Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion

Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy