Post-transcriptional regulation in cancer progression : Microenvironmental control of alternative splicing and translation

Abstract

The microenvironment acts as a conduit for cellular communication, delivering signals that direct development and sustain tissue homeostasis. In pathologies such as cancer, this integral function of the microenvironment is hijacked to support tumor growth and progression. Cells sense the microenvironment via signal transduction pathways culminating in altered gene expression. In addition to induced transcriptional changes, the microenvironment exerts its effect on the cell through regulation of post-transcriptional processes including alternative splicing and translational control. Here we describe how alternative splicing and protein translation are controlled by microenvironmental parameters such as oxygen availability. We also emphasize how these pathways can be utilized to support processes that are hallmarks of cancer such as angiogenesis, proliferation, and cell migration. We stress that cancer cells respond to their microenvironment through an integrated regulation of gene expression at multiple levels that collectively contribute to disease progression.

Fig. 1

A schematic of how fate decisions are regulated in part by microenvironmental factors. The large blue horizontal arrow represents how differentiated cells can become dedifferentiated during tumorigenesis. This process involves cellular responses to the microenvironment that include changes in transcription, as well as post-transcriptional processes such as alternative splicing and translation. An example in which expression of one protein isoform is increased (green arrow) and the alternatively-spliced isoform is decreased (red arrow) is shown

Fig. 2

Major types of alternative splicing. Orange bars represent constitutive exons always included in the processed mRNA transcript. Blue bars represent alternative exons, and grey bars represent introns. Diagonal lines join splice donor sites at the 5′ end of an intron and splice acceptor sites at the 3′ end of an intron, flanking the intronic sequence to be spliced out. Splicing sites along the top of the transcript denote one possible transcript, while those along the bottom denote the other isoform for these simple cases

Fig. 3

A summary of how microenvironmental factors typically affect signaling pathways regulating alternative splicing and translation. Blue arrows indicate activating effects, although not necessarily an active protein, and red bars indicate inhibiting effects. Extracellular activation of PI3K causes an activation of AKT resulting in the phosphorylation of SR proteins and mTOR, directly altering splicing patterns and the dynamics of translation, respectively. Inhibition of mTOR enhances cap-independent translation through derepression of 4EBP causing inactivation of eIF4E. The RAS/MEK pathway is also involved in promoting cap-independent translation through other eIF proteins. Components of both of these pathways (AKT and ERK), also phosphorylate SR proteins, altering their RNA binding specificities and thus patterns of splicing