There are several human genes that may encode
proteins whose functions remain unknown. To find clues to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkpoint complex. Phenotypes that were provoked by the expression of a human C18orf26
protein in the mutant yeast encouraged further characterization of this
protein in human cells. This
protein was designated dynAP (
dynactin-associated
protein) because of its interaction with
dynactin subunits that comprised a microtubule-based motor
protein complex. The dynAP is a transmembrane
protein localizing to Golgi apparatus and plasma membrane in a microtubule-dependent manner. This
protein was expressed in half of human
cancer cell lines but barely in normal human fibroblasts tested. The SV40-transformed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also known as
protein kinase B) by promoting Ser⁴⁷³ phosphorylation required for the full activation, whereas knockdown of dynAP abolished this activation. The
ergosterol-related compounds identified by the yeast cell-based high-throughput screen abrogated activation of Akt and induced apoptosis in a dynAP-dependent manner. We propose a possible advantage of dynAP expression in
cancer cells; the survival of
cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining high rates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, and thereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target for
cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs.