In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.
The initiation and elongation stages of translation are directed by codon-anticodon interactions. In contrast, a release factor protein mediates stop codon recognition prior to polypeptide chain release. Previous studies have identified specific regions of eukaryotic release factor one (eRF1) that are important for decoding each stop codon. The cavity model for eukaryotic stop codon recognition suggests that three binding pockets/cavities located on the surface of eRF1's domain one are key elements in stop codon recognition. Thus, the model predicts that amino acid changes in or near these cavities should influence termination in a stop codon-dependent manner. Previous studies have suggested that the TASNIKS and YCF motifs within eRF1 domain one play important roles in stop codon recognition. These motifs are highly conserved in standard code organisms that use UAA, UAG, and UGA as stop codons, but are more divergent in variant code organisms that have reassigned a subset of stop codons to sense codons. In the current study, we separately introduced TASNIKS and YCF motifs from six variant code organisms into eRF1 of Saccharomyces cerevisiae to determine their effect on stop codon recognition in vivo. We also examined the consequences of additional changes at residues located between the TASNIKS and YCF motifs. Overall, our results indicate that changes near cavities two and three frequently mediated significant effects on stop codon selectivity. In particular, changes in the YCF motif, rather than the TASNIKS motif, correlated most consistently with variant code stop codon selectivity.
The heterogeneous nature of prostate cancer tumors is thought to play an important role in the decreased effectiveness of existing therapies. Tumor initiating cells (TICs) are capable of self-renewal and comprise a subset of the tumor mass. These cells are proposed to drive the growth and metastasis of tumors, and are considered to be resistant to traditional cytotoxic and targeted therapies. Several studies have shown that NF-κB signaling is increased in recurrent prostate cancer and enriched in prostate TICs. We sought to determine the potential of an IKK/NF-κB-driven mechanism for inherent or acquired resistance by IKK-mediated control of a subset of prostate tumor initiating cells. These studies were performed by using established prostate cancer cell lines, murine prostate organoids, and a murine prostate cancer animal model. We have found that inhibition of IKKα and IKKβ, upstream regulators of noncanonical and canonical NF-κB signaling, block self-renewal of several PTEN-deficient prostate cancer cell lines. Furthermore, we have also found that IKK is important for tumorigenicity and stemness seen in prostate cancer cells as measured by colony formation and extreme limiting dilution assays. Loss of canonical NF-κB (p65/RelA) decreased stemness while loss of noncanonical did not alter tumorsphere formation. Interestingly, Pten-/- tumors with loss of Ikkα or Ikkβ displayed decreased levels of self-renewing cells as measured by CD49fhigh expression, a known prostate basal cell marker. Isolated murine Pten-/- cells were 2x more efficient than Pten-/-Ikkα-/- or Pten-/-Ikkβ-/- cells in forming prostate organoids suggesting that loss of Ikk decreased the number of self-renewing cells needed for formation. Taken together, we conclude that IKK-mediated signaling is important for maintenance of prostate tumor initiating cells and further studies will address whether IKK-mediated signaling provides a mechanism for evading current therapies. Note: This abstract was not presented at the meeting. Citation Format: Sara E. Conard, Aaron Ebbs, Albert S. Baldwin. IKK-mediated signaling controls prostate tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2877. doi:10.1158/1538-7445.AM2017-2877
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