Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth.
Bottom Line: Conversely, phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion.Finally, Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly.These findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics.
Affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.Show MeSH
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Mentions: Human CK1δ and CK1ε have ∼65% sequence identity and 85% sequence similarity to Hrr25, and both have been implicated in 40S ribosome maturation (Zemp et al., 2014). To assess the effect of CK1δ/CK1ε inhibition on ribosome assembly and cell growth, we used the small molecule inhibitor SR-3029, a potent and highly specific inhibitor of CK1δ and CK1ε (Bibian et al., 2013). For our experiments, we used MDA-MB-231 triple-negative human breast cancer cells, which express high levels of CK1δ, are sensitive to knockdown of CK1δ (but not to silencing of CK1ε), and are highly sensitive to SR-3029 (Rosenberg et al., 2015). As expected, treatment of these cells with low concentrations of SR-3029 (30 nM) led to marked and rapid reductions in cell growth (Fig. 6 A). This is consistent with previous findings that both CK1δ and CK1ε have essential functions in human cells (Knippschild et al., 2014).
Affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.