Davide Ruggero, PhD

Professor in Residence
Department of Urology
Research Overview: 

Our research is centered on understanding the molecular mechanisms by which impairments in accurate control of mRNA translation, cell growth, and overall cellular protein synthesis rates lead to cancer. While it is commonly accepted that oncogenic signaling deregulates the transcriptional profile of neoplastic cells, our research has demonstrated a pivotal role for impairments in the translational efficiency of specific existing mRNA species at the post-transcription level towards cancer initiation. Global analysis of the deregulated proteome during cancer formation utilizing novel polysome microarrays pioneered by the Ruggero lab indicates that control of protein production provides a highly specific, robust, and rapid response to oncogenic stimuli. The mRNAs translationally affected encode proteins involved in cell-cell interaction, cell differentiation, signal transduction, and growth control. These findings strongly suggest that a radical shift in the composition of mRNAs associated with actively translating polysomes may lead to an immediate neoplastic phenotype upon an oncogenic lesion. Our research is uncovering that the direct effect on the proteome may serve as common mechanism elicited by multiple oncogenic signals (ie. PTEN/AKT/TOR, Ras, Myc) to cause cellular transformation and may overshadow the effect on the transcriptosome.

Our lab has generated the first mouse models for components of the translation machinery, including translation initiation factors and structural components of the ribosome, found muted in human disease and cancer. Utilizing biochemical, molecular, and genetic approaches within the context of these unique animal models, will continue to address: (1) Which specific steps of protein synthesis control, when deregulated, contribute to cancer initiation and what are the rate limiting steps in protein biosynthesis that are regulated by mitogens and growth factors? (2) What are the target mRNAs, which are affected by aberrant protein translation in neoplastic cells and do they contain specific signatures in their untranslated regions? (3) How is control of translation initiation coupled to cell growth and proliferation and can we apply this knowledge to the discovery of novel therapeutic agents that target the deregulated translation machinery in cancer? The implications of these results will be important in the design of a new generation of compounds that modulate the cellular proteome at the post-genomic level and act as cancer therapeutic agents.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Human Genetics
Research Summary: 
Dynamics of translation control in gene expression, cancer, and disease

Websites

Publications: 

Localization of a TORC1-eIF4F translation complex during CD8+ T cell activation drives divergent cell fate.

Molecular cell

Liedmann S, Liu X, Guy CS, Crawford JC, Rodriguez DA, Kuzuoglu-Öztürk D, Guo A, Verbist KC, Temirov J, Chen MJ, Ruggero D, Zhang H, Thomas PG, Green DR

Protein synthesis control in cancer: selectivity and therapeutic targeting.

The EMBO journal

Kovalski JR, Kuzuoglu-Ozturk D, Ruggero D

ERα is an RNA-binding protein sustaining tumor cell survival and drug resistance.

Cell

Xu Y, Huangyang P, Wang Y, Xue L, Devericks E, Nguyen HG, Yu X, Oses-Prieto JA, Burlingame AL, Miglani S, Goodarzi H, Ruggero D

A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies.

Developmental cell

Tiu GC, Kerr CH, Forester CM, Krishnarao PS, Rosenblatt HD, Raj N, Lantz TC, Zhulyn O, Bowen ME, Shokat L, Attardi LD, Ruggero D, Barna M