Showing papers by "Davide Ruggero published in 2012"
TL;DR: A clinically relevant ATP site inhibitor of mTOR, INK128, is developed, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure.
Abstract: The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.
1,151 citations
TL;DR: It is reported that sustained IRE1α RNase activation caused rapid decay of select microRNAs that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway.
Abstract: The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein-folding demand leads to "ER stress," and activates IRE1α, an ER transmembrane kinase-endoribonuclease (RNase). IRE1α promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1α RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, and -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1α endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1α regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.
547 citations
TL;DR: A role for UPR is established as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c- myc overexpression.
Abstract: The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.
321 citations
TL;DR: Current research will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis.
Abstract: The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as “ribosomopathies” associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis.
320 citations
TL;DR: Emerging studies provide interesting insight into how deregulations in RNA polymerase I activity may lead to tumorigenesis and suggest that new drugs targeting ribosomal DNA transcription may hold great promise for the treatment of cancer.
Abstract: Key signaling pathways (such as phosphoinositide 3-kinase, Myc, and RAS) act as sensors of energy, stress, and nutrient availability and integrate these inputs to directly control ribosome production and gene expression at the translational level. This activity is normally directly coupled to cell growth, division, and survival. However, it remains poorly understood the extent to which changes in ribosome number and nucleolar integrity downstream of these key signaling pathways contribute to their oncogenic activity. Emerging studies provide interesting insight into how deregulations in RNA polymerase I activity may lead to tumorigenesis and suggest that new drugs targeting ribosomal DNA transcription may hold great promise for the treatment of cancer.
104 citations
TL;DR: The author would like to apologize for inadvertently omitting to indicate this and notes that Figures 1 and 2 and Table 1 are also adapted and extended from versions in the earlier article.
Abstract: Cold Spring Harbor Perspect Biol 10.1101/cshperspect.a012336
Early sections of the text are based on an article written by this author that was previously published in Current Opinion in Genetics and Development (Stumpf and Ruggero 2011). The author would like to apologize for inadvertently omitting to indicate this and notes that Figures 1 and 2 and Table 1 are also adapted and extended from versions in the earlier article.
6 citations
01 Jan 2012
TL;DR: This chapter will review several biophysical approaches that have been employed to study the role of rRNA pseudouridine modifications in translation control and provide mechanistic insights into how pseudouridylation of r RNA, when deregulated, may alter the expression of specific mRNAs contributing to certain pathological features of human diseases.
Abstract: Posttranscriptional ribosomal RNA (rRNA) modifications are present in all organisms and appear to be essential for the control of protein synthesis in the majority of species. The isomerization of uridine to pseudouridine on rRNA has important implications not only for ribosome structure but also for ribosome function. Structural and functional studies of both prokaryotic and eukaryotic ribosomes have revealed that pseudouridylation may regulate ribosome activity by facilitating extensive rRNA conformational changes. Furthermore, recent findings indicate that pseudouridylation of rRNA has an important regulatory role in modulating gene expression of specific mRNAs at the translational level. In this chapter we will review several biophysical approaches that have been employed to study the role of rRNA pseudouridine modifications in translation control. Additionally, we will provide mechanistic insights into how pseudouridylation of rRNA, when deregulated, may alter the expression of specific mRNAs contributing to certain pathological features of human diseases. Finally, we will discuss our perspectives on several outstanding questions related to the role of rRNA modifications in translational control.
4 citations