Results: 2

Figure 1

Figure 1. Deregulations in translational control can contribute to each step of cellular transformation and tumor progression. From: The Cancerous Translation Apparatus.

A.) Upon receiving an oncogenic insult (represented by a lightning bolt), e.g. Myc overexpression or PI3K hyperactivation, cells induce ribosome biogenesis and global protein synthesis that leads to increased cell size, coupled to cell division. Upon oncogenic stress, cells initiate a tumor suppressive response, associated with increased IRES mediated translation, leading to cell cycle arrest and senescence. In order to overcome the barrier of oncogene-induced senescence, cells acquire additional mutations (secondary hits, represented by lightning bolt). One mechanism for this is decreased translation from the CDK11/p58 IRES during mitosis, resulting from Myc hyperactivation, that leads to genome instability. B.) Once established, a primary tumor will undergo unrestrained growth, leading to a stress response associated with depletion of oxygen and essential nutrients from the core of the tumor. Lack of key nutrients, such as growth factors, often leads to increased apoptosis (skulls). Tumor cells upregulate cap-independent translation of anti-apoptotic factors (such as Bcl-2 and XIAP) as a mechanism to promote survival (blocked skulls). To bypass stress caused by low levels of oxygen in the tumor, cells induce cap-independent translation of neo-angiogenesis promoting factors such as VEGF.

Craig R. Stumpf, et al. Curr Opin Genet Dev. 2011 August;21(4):474-483.
Figure 2

Figure 2. Oncogenes and Tumor Suppressors are translationally regulated through specific regulatory elements in their mRNAs. From: The Cancerous Translation Apparatus.

Depictions of cis-regulatory elements present in oncogenes (top) and tumor suppressor (bottom) mRNAs. Examples of regulated mRNAs are given (grey boxes). The cap binding protein eIF4E binds the 5’ cap of mRNAs. Increased eIF4E activity recruits eIF4G and the eIF4A helicase to unwind (green arrow) structured elements in the 5’UTR of poorly translated mRNAs, increasing the expression of many growth promoting and pro-survival genes, such as Mcl-1. Another group of structural elements that direct translational regulation are IRES elements. IRES elements promote cap-independent protein synthesis of both tumor suppressors (p53) and pro-survival factors (XIAP) during different stages of tumor development (see Figure 1). IRES Trans-Acting Factors (ITAFs) modulate translational regulation directed by specific IRES elements. Upstream Open Reading Frames (uORF) are present in select mRNAs and inhibit protein synthesis by preventing the ribosome from scanning to the start codon. Translation of growth promoting factors, such as Mdm2 and Her-2, is limited by uORFs. Additionally, a region in the 3’UTR of the Her-2 mRNA can inhibit uORF mediated repression of translation. 3’UTRs contain many distinct elements that interact with RNA binding proteins (RBPs) and miRNAs to promote or inhibit translation. One interesting example is the regulation of p53 translation mediated by base pairing interactions between elements in the 5’ and 3’ UTRs of the p53.

Craig R. Stumpf, et al. Curr Opin Genet Dev. 2011 August;21(4):474-483.

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