Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

Sriram, Ashwin; Bohlen, Jonathan; Teleman, Aurelio A.

doi:10.15252/embr.201845947

Cited by 76 publications

(48 citation statements)

References 270 publications

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“…We seem poised for molecular dissection of CD and CI translation to identify functional complexes (RNA and protein) and their roles in differentiation. This initiative bears some resemblance to emerging interest in CI vs. CD translation mechanisms in oncogenesis and cancer progression [155,156,157]. Germ cells/embryos and cancers have revealed over time many remarkable parallels in metabolism, cell cycle and growth, so parallels in translation mechanisms might also be expected.…”

Section: Discussionmentioning

confidence: 89%

Cap-Independent mRNA Translation in Germ Cells

Keiper¹

2019

IJMS

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Cellular mRNAs in plants and animals have a 5′-cap structure that is accepted as the recognition point to initiate translation by ribosomes. Consequently, it was long assumed that the translation initiation apparatus was built solely for a cap-dependent (CD) mechanism. Exceptions that emerged invoke structural damage (proteolytic cleavage) to eukaryotic initiation factor 4 (eIF4) factors that disable cap recognition. The residual eIF4 complex is thought to be crippled, but capable of cap-independent (CI) translation to recruit viral or death-associated mRNAs begrudgingly when cells are in great distress. However, situations where CI translation coexists with CD translation are now known. In such cases, CI translation is still a minor mechanism in the major background of CD synthesis. In this review, I propose that germ cells do not fit this mold. Using observations from various animal models of oogenesis and spermatogenesis, I suggest that CI translation is a robust partner to CD translation to carry out the translational control that is so prevalent in germ cell development. Evidence suggests that CI translation provides surveillance of germ cell homeostasis, while CD translation governs the regulated protein synthesis that ushers these meiotic cells through the remarkable steps in sperm/oocyte differentiation.

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Section: Discussionmentioning

confidence: 89%

Cap-Independent mRNA Translation in Germ Cells

Keiper¹

2019

IJMS

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“…Likewise, recent studies have highlighted the altered regulation of translation in various cancers (82), including CRC (83). Indeed, alternative mechanisms of translation, such as leaky scanning, re-initiation and IRES usage seem to be favored, and this has been associated with, higher cell proliferation, invasion and resistance to apoptosis and therapy (84). In this regard, the expression of BAG-1, recently described as a colorectal anti-apoptotic oncogene, is regulated by alternative translation mechanisms, and thus represents a good model to study how a rG4, along with the different regulatory elements of the 5′UTR, controls protein synthesis.…”

Section: Resultsmentioning

confidence: 99%

G-quadruplex located in the 5′UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance

Jodoin

Carrier

Rivard

et al. 2019

Nucleic Acids Research

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The anti-apoptotic BAG-1 protein isoforms are known to be overexpressed in colorectal tumors and are considered to be potential therapeutic targets. The isoforms are derived from alternative translation initiations occuring at four in-frame start codons of a single mRNA transcript. Its 5′UTR also contains an internal ribosome entry site (IRES) regulating the cap-independent translation of the transcript. An RNA G-quadruplex (rG4) is located at the 5′end of the BAG-1 5′UTR, upstream of the known cis-regulatory elements. Herein, we observed that the expression of BAG-1 isoforms is post-transcriptionally regulated in colorectal cancer cells and tumors, and that stabilisation of the rG4 by small molecules ligands reduces the expression of endogenous BAG-1 isoforms. We demonstrated a critical role for the rG4 in the control of both cap-dependent and independent translation of the BAG-1 mRNA in colorectal cancer cells. Additionally, we found an upstream ORF that also represses BAG-1 mRNA translation. The structural probing of the complete 5′UTR showed that the rG4 acts as a steric block which controls the initiation of translation at each start codon of the transcript and also maintains the global 5′UTR secondary structure required for IRES-dependent translation.

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“…This implies that the ribosome can be recruited to the 3′ UTR, enhancing protein synthesis from the upstream sequence [117]. Intriguingly, mRNAs that contain IRES are preferentially translated when cap-dependent translation is inhibited, during cell differentiation, proliferation, and under hypoxic conditions and nutrient limitation [119]. A recent PubMed search and clustering analysis revealed that approximately 21% of transcription factor mRNAs, 15% of growth factor mRNAs, and 22% of receptor and transporter mRNAs are prone to be translated via an IRES-dependent way [108].…”

Section: Protein Synthesis and Cancermentioning

confidence: 99%

Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control

Kim

2019

Biomolecules

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Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and the dysregulation of translation, which in turn, leads to aberrant protein synthesis. In addition, the machinery that is involved in protein synthesis plays critical roles in stem cell fate determination. In the current review, recent advances in the understanding of translational control, especially translational initiation in cancer development and stem cell fate control, are described. Therapeutic targets of mRNA translation such as eIF4E, 4EBP, and eIF2, for cancer treatment or stem cell fate regulation are reviewed. Upstream signaling pathways that regulate and affect translation initiation were introduced. It is important to regulate the expression of protein for normal cell behavior and development. mRNA translation initiation is a key step to regulate protein synthesis, therefore, identifying and targeting molecules that are critical for protein synthesis is necessary and beneficial to develop cancer therapeutics and stem cells fate regulation.

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Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

Cited by 76 publications

References 270 publications

Cap-Independent mRNA Translation in Germ Cells

Cap-Independent mRNA Translation in Germ Cells

G-quadruplex located in the 5′UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance

Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control

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