Discovery ovel Human Dynactin-Associated Protein , dynAP , motes Activation of Akt , and Ergosterol-Related pounds Induce dynAP-Dependent Apoptosis of Ther an Cancer Cells

ownload re are several human genes that may encode proteins whose functions remain unknown. To find to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkcomplex. Phenotypes that were provoked by the expression of a human C18orf26 protein in the t yeast encouraged further characterization of this protein in human cells. This protein was ated dynAP (dynactin-associated protein) because of its interaction with dynactin subunits that ised a microtubule-based motor protein complex. The dynAP is a transmembrane protein localizing lgi apparatus and plasma membrane in a microtubule-dependent manner. This protein was sed in half of human cancer cell lines but barely in normal human fibroblasts tested. The SV40ormed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also as protein kinase B) by promoting Ser phosphorylation required for the full activation, whereas down of dynAP abolished this activation. The ergosterol-related compounds identified by the cell–based high-throughput screen abrogated activation of Akt and induced apoptosis in a -dependent manner. We propose a possible advantage of dynAP expression in cancer cells; the al of cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining ates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, ereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target and th for cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs. Mol Cancer Ther; 9(11); 2934–42. ©2010 AACR.