Translation initiation and its deregulation during tumorigenesis (original) (raw)

Translation Regulation as a Therapeutic Target in Cancer

Cancer Research, 2012

Protein synthesis is a vital cellular process that regulates growth and metabolism. It is controlled via signaling networks in response to environmental changes, including the presence of nutrients, mitogens, or starvation. The phosphorylation state of proteins involved in translation initiation is a limiting factor that regulates the formation or activity of translational complexes. In cancer cells, hyperactivated signaling pathways influence translation, allowing uncontrolled growth and survival. In addition, several components of translation initiation have been found to be mutated, posttranslationally modified, or differentially expressed, and some act as oncogenes in cancer cells. Translational alterations can increase the overall rate of protein synthesis as well as activate regulatory mechanisms leading to the translation of specific messenger RNAs for proteins that promote cancer progression and survival. Many recent studies investigating such mechanisms have produced ideas ...

A widespread alternate form of cap-dependent mRNA translation initiation

Nature communications, 2018

Translation initiation of most mammalian mRNAs is mediated by a 5' cap structure that binds eukaryotic initiation factor 4E (eIF4E). However, inactivation of eIF4E does not impair translation of many capped mRNAs, suggesting an unknown alternate mechanism may exist for cap-dependent but eIF4E-independent translation. We show that DAP5, an eIF4GI homolog that lacks eIF4E binding, utilizes eIF3d to facilitate cap-dependent translation of approximately 20% of mRNAs. Genome-wide transcriptomic and translatomic analyses indicate that DAP5 is required for translation of many transcription factors and receptor capped mRNAs and their mRNA targets involved in cell survival, motility, DNA repair and translation initiation, among other mRNAs. Mass spectrometry and crosslinking studies demonstrate that eIF3d is a direct binding partner of DAP5. In vitro translation and ribosome complex studies demonstrate that DAP5 and eIF3d are both essential for eIF4E-independent capped-mRNA translation. ...

CK1 Delta Is an mRNA Cap-Associated Protein That Drives Translation Initiation and Tumor Growth

ABSTRACTWhether translation is differentially regulated across liquid and solid tumors remains poorly understood. Here we report the discovery that Casein Kinase 1 delta (CK1δ) plays a key role in regulating translation initiation in blood cancers, but interestingly, not in solid tumors. In lymphomas CK1δ is a key positive regulator of 4E-BP1 and p70S6K phosphorylation, assembly of eIF4F, and translation initiation. Furthermore, CK1δ is pulled down by m7GTP-agarose that mimics the mRNA m7G cap, consistent with the regulatory role of CK1δ in translation initiation. Targeting CK1δ using a small molecule inhibitor, namely SR-3029, potently kills lymphoma cell lines and primary lymphoma cells across histology subtypes. While SR-3029 shares with mTORC1 inhibitors the overlapping mechanism of repressing 4E-BP1 and p70S6K/RPS6 phosphorylation, the kinetics of repression is slow with SR-3029 and fast with mTORC1 inhibitors such as Torin-1. Remarkably, it is slower-acting SR-3029, but not fa...