| Autor: |
Gholkar AA; Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States., Gimeno TV; Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States., Edgemon JE; Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States., Sim MS; Department of Medicine Statistics Core, University of California, Los Angeles, California 90095, United States.; Department of Medicine's Division of General Internal Medicine and Health Services Research, University of California, Los Angeles, California 90095, United States., Torres JZ; Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, United States.; Molecular Biology Institute, University of California, Los Angeles, California 90095, United States. |
| Abstrakt: |
Primary cilia are membrane-covered microtubule-based structures that protrude from the cell surface and are critical for cell signaling and homeostasis during human development and adulthood. Dysregulation of cilia formation, length, and function can lead to a spectrum of human diseases and syndromes known as ciliopathies. Although some genetic and chemical screens have been performed to define important factors that modulate cilia biogenesis and length control, there are currently no clinical treatments that restore cilia length in patients. We report that the microtubule-targeting agent MI-181(mitotic inhibitor-181) is a potent modulator of cilia length and biogenesis. Treatment of retinal pigment epithelial-1 cells with MI-181 induced an increase in the average size of cilia and in the percent ciliated cells under nonstarved conditions. Importantly, MI-181 was effective at rescuing cilia length and ciliation defects in cells that had been treated with the intraflagellar transport inhibitor Ciliobrevin D or the O-GlcNAc transferase inhibitor OSMI-1. Most importantly, MI-181 induced an increase in cilia length and restored ciliation in cells with compromised shortened cilia at low nanomolar concentrations and did not show an inhibitory response at high concentrations. Therefore, MI-181 represents a lead molecule for developing drugs targeting ciliopathies characterized by shortened cilia. |
