PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.     

Leibniz and the post-Copernican universe. Koyré revisited

This paper employs the revised conception of Leibniz emerging from recent research to reassess critically the ‘radical spiritual revolution’ which, according to Alexandre Koyré’s landmark book, From the closed world to the infinite universe (1957) was precipitated in the seventeenth century by the revolutions in physics, astronomy, and cosmology. While conceding that the cosmological revolution necessitated a reassessment of the place of value-concepts within cosmology, it argues that this reassessment did not entail a spiritual revolution of the kind assumed by Koyré, in which ‘value-concepts, such as perfection, harmony, meaning and aim’ were shed from the conception of the structure of the universe altogether. On the contrary, thanks to his pioneering intuition of the distinction between physical and metaphysical levels of explanation, Leibniz saw with great clarity that a scientific explanation of the universe which rejected the ‘closed world’ typical of Aristotelian cosmology did not necessarily require the abandonment of key metaphysical doctrines underlying the Aristotelian conception of the universe. Indeed the canon of value-concepts mentioned by Koyré—meaning, aim, perfection and harmony—reads like a list of the most important concepts underlying the Leibnizian conception of the metaphysical structure of the universe. Moreover, Leibniz’s universe, far from being a universe without God—because, as Clarke insinuated, it does not need intervention from God—is a universe which in its deepest ontological fabric is interwoven with the presence of God.     

A conserved microRNA module exerts homeotic control over Petunia hybrida and Antirrhinum majus floral organ identity

It is commonly thought that deep phylogenetic conservation of plant microRNAs (miRNAs) and their targets indicates conserved regulatory functions. We show that the blind (bl) mutant of Petunia hybrida and the fistulata (fis) mutant of Antirrhinum majus, which have similar homeotic phenotypes, are recessive alleles of two homologous miRNA-encoding genes. The BL and FIS genes control the spatial restriction of homeotic class C genes to the inner floral whorls, but their ubiquitous early floral expression patterns are in contradiction with a potential role in patterning C gene expression. We provide genetic evidence for the unexpected function of the MIRFIS and MIRBL genes in the center of the flower and propose a dynamic mechanism underlying their regulatory role. Notably, Arabidopsis thaliana, a more distantly related species, also contains this miRNA module but does not seem to use it to confine early C gene expression to the center of the flower.     

Role of nucleophosmin in embryonic development and tumorigenesis

Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1(hy/hy) < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1(hy/hy) mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis.     

Guggulsterol-like steroids from the Mediterranean gorgonianLeptogorgia sarmentosa

Summary Several polyoxygenated steroids (1, 2, 3) have been isolated from the marine gorgonianLeptogorgia sarmentosa. One of these (1) is the known guggulsterol III, previously found in the pharmacologically active resin from the treeCommiphora mukul; the others,2 and3, have not been found before in nature, and are closely related to1. During the structural work apparent anomalies in the CMR-spectra of1 were observed.The authors are grateful to Prof. Sukh Dev for the PMR-spectra of guggulsterol III. Thanks are also due to Zoological Station (Naples), for the collection of the gorgonian, to Centro Metodologie Chimico-Fisiche, Università di Napoli, for recording PMR-spectra on WH-270 Superconducting Spectrometer-Bruker, to Mr C. Di Pinto for the CMR-spectra and to Mr A. Milone for the MS spectral measurements.