The cancerous translation apparatus

https://doi.org/10.1016/j.gde.2011.03.007Get rights and content

Deregulations in translational control are critical features of cancer initiation and progression. Activation of key oncogenic pathways promotes rapid and dramatic translational reprogramming, not simply by increasing overall protein synthesis, but also by modulating specific mRNA networks that promote cellular transformation. Additionally, ribosomopathies caused by mutations in ribosome components alter translational regulation leading to specific pathological features, including cancer susceptibility. Exciting advances in our understanding of translational control in cancer have illuminated a striking specificity innate to the translational apparatus. Characterizing this specificity will provide novel insights into how cells normally utilize translational control to modulate gene expression, how it is deregulated in cancer, and how these processes can be targeted to develop new cancer therapies.

Highlights

► Deregulation of translational control is critical for cancer development. ► Mutations in ribosome components are associated with cancer susceptibility syndromes. ► Alterations in translational control impinge on distinct steps of cellular transformation. ► Translational deregulation of specific mRNAs contributes to tumor initiation and progression. ► Specific regulatory elements control translation of oncogenes and tumor suppressors.

Introduction

Decades of research into the molecular programs that govern cellular transformation have mainly focused on the cancer transcriptome. For example, the microarray era has made it possible to catalogue genome-wide variations in the repertoire of transcriptional outputs downstream of specific oncogenic signaling pathways. Ultimately, however, these studies have fallen short in interrogating the end product of gene expression at the level of protein synthesis. A new and critical pipeline into understanding cancer evolution is the growing body of evidence showing that key oncogenic pathways such as Myc and PI3K have monopolized the translational machinery to direct specific post-transcriptional changes in gene expression directly at the level of protein production (Figure 1). In addition, an entire class of inherited syndromes collectively referred to as “ribosomopathies” is characterized by increased cancer susceptibility and harbor mutations in distinct components of the translational apparatus. The realization that there is a post-genomic control mechanism in cancer development has fundamental implications in the design of new cancer therapies that may eradicate the abnormal translational program of cancer cells.

Section snippets

Do mutations in the ribosome cause cancer?

A number of mutations in ribosomal proteins or biogenesis factors have been identified that correlate with increased cancer incidence in humans (Table 1). Animal models harboring mutations similar to those found in humans faithfully recapitulate these features and have shed light onto how specific mutations in the translational machinery lead to human pathologies.

One important example of how defects in the ribosome contribute to specific disease pathologies and cancer susceptibility is X-linked

How does manipulation of the translational machinery by oncogenic signaling promote cancer?

Ribosome biogenesis and global protein synthesis are tightly and dynamically regulated to accommodate the growth demands of a cell. Indeed, an increase in cell mass is a prerequisite for accurate cell division. This is achieved by signaling pathways that simultaneously sense energy, stress, nutrient availability, as well as growth factors, and integrate these inputs to direct control of ribosome production and activity. One of the primary reasons for this cross talk is to integrate external

How does aberrant translation promote cancer – is it all just growth?

In most representations of cancer development, deregulations in protein synthesis are simply depicted by a generic arrow that culminates in cell growth. While this may certainly be one of the mechanisms by which deregulations in protein synthesis lead to cancer development, it is not the full story. Recent studies are clearly showing that oncogenic signaling may monopolize the translational machinery at almost every stage of cancer initiation and development for very specific and distinct

Concluding remarks

We are only beginning to understand the broad implications of translational regulation as it relates to cancer biology. Oncogenic signaling appears to monopolize translational control at almost every stage of cancer initiation and development for very specific and distinct cellular outcomes (Figure 1). Currently there is a shift towards a growing realization of the importance of specificity in translational regulation mediated by the core components of the translational apparatus. Key among

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Maria Barna and members of the Ruggero lab for input and critical reading of this review. Thank you to Kimhouy Tong for editing the manuscript. We apologize to the many scientists whose work we were unable to cite. Dr. Davide Ruggero is a Leukemia & Lymphoma Society Scholar. This work is supported by NIH R01 HL085572 (D.R.) and NIH R01 CA140456 (D.R.).

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