<em>MHO1,</em> an Evolutionarily Conserved Gene, Is Synthetic Lethal with <em>PLC1;</em> Mho1p Has a Role in Invasive Growth

Abstract

<div><p>The novel protein Memo (<u>M</u>ediator of <u>E</u>rbB2 driven cell <u>mo</u>tility) was identified in a screen for ErbB2 interacting proteins and found to have an essential function in cell motility. Memo is evolutionarily conserved with homologs found in all branches of life; the human and yeast proteins have a similarity of >50%. In the present study we used the model organism <em>S. cerevisiae</em> to characterize the Memo-homologue Mho1 (Yjr008wp) and to investigate its function in yeast. In a synthetic lethal screen we found <em>MHO1</em> as a novel synthetic lethal partner of <em>PLC1,</em> which encodes the single phospholipase C in yeast. Double-deleted cells lacking <em>MHO1</em> and <em>PLC1,</em> proliferate for up to ten generations. Introduction of human Memo into the <em>memoΔplc1Δ</em> strain rescued the synthetic lethal phenotype suggesting that yeast and human proteins have similar functions. Mho1 is present in the cytoplasm and the nucleus of yeast cells; the same distribution of Memo was found in mammalian cells. None of the Memo homologues have a characteristic nuclear localization sequence, however, a conserved nuclear export sequence is found in all. In mammalian cells, blocking nuclear export with Leptomycin B led to nuclear Memo accumulation, suggesting that it is actively exported from the nucleus. In yeast <em>MHO1</em> expression is induced by stress conditions. Since invasive growth in <em>S. cerevisiea</em> is also stress-induced, we tested Mho1's role in this response. <em>MHO1</em> deletion had no effect on invasion induced by nutrient deprivation, however, Mho1 overexpression blocked the invasive ability of yeast cells, suggesting that Mho1 might be acting in a dominant negative manner. Taken together, our results show that <em>MHO1</em> is a novel synthetic lethal interactor with <em>PLC1</em>, and that both gene products are required for proliferation. Moreover, a role for Memo in cell motility/invasion appears to be conserved across species.</p> </div