Isolation of a Mammalian Homologue of a Fission Yeast Differentiation Regulator

Abstract

In the fission yeast Schizosaccharomyces pombe the nrd1⁺ gene encoding an RNA binding protein negatively regulates the onset of differentiation. Its biological role is to block differentiation by repressing a subset of the Ste11-regulated genes essential for conjugation and meiosis until the cells reach a critical level of nutrient starvation. By using the phenotypic suppression of the S. pombetemperature-sensitive pat1 mutant that commits lethal haploid meiosis at the restrictive temperature, we have cloned ROD1, a functional homologue of nrd1⁺, from rat and human cDNA libraries. Like nrd1⁺, ROD1 encodes a protein with four repeats of typical RNA binding domains, though its amino acid homology to Nrd1 is limited. When expressed in the fission yeast,ROD1 behaves in a way that is functionally similar to nrd1⁺, being able to repress Ste11-regulated genes and to inhibit conjugation upon overexpression. ROD1is predominantly expressed in hematopoietic cells or organs of adult and embryonic rat. Like nrd1⁺ for fission yeast differentiation, overexpressed ROD1 effectively blocks both 12-O-tetradecanoyl phorbol-13-acetate-induced megakaryocytic and sodium butyrate-induced erythroid differentiation of the K562 human leukemia cells without affecting their proliferative ability. These results suggest a role for ROD1 in differentiation control in mammalian cells. We discuss the possibility that a differentiation control system found in the fission yeast might well be conserved in more complex organisms, including mammals.

ACKNOWLEDGMENT

This work was supported by grants from the Ministry of Education, Science and Culture, Tokyo, Japan.