Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse

Genetic alterations of FKHR (FOXO1), AF6q21 (FOXO2), and AFX (FOXO4), close ly related members of the forkhead family of DNA binding proteins, in human cancers has suggested they play a role in the regulation of cellular diffe rentiation or proliferation. In order to elucidate the function of this gen e subfamily during mammalian development, we have identified and characteri zed three novel mouse genes; Fkhr1 (Foxo1), Fkhr2 (Foxo3), and Afxh (Foxo4) , which are closely related to the human FKHR (Foxo1), AF6q21 (FOXO2), and AFX (FOXO4) genes, respectively. The genes are each expressed both during d evelopment and in the adult with distinct patterns ranging from ubiquitous [Fkhr2 (Foxo3)] to tissue-specific [Afxh (Foxo4)]. Selection of high-affini ty DNA-binding sites from a pool of degenerate oligonucleotides demonstrate d that the proteins encoded by these genes recognize a core sequence [(T/A) (A/T) A A C A] similar to that recognized by other forkhead domain-contain ing proteins. We have also identified additional FKHR-related genes express ed during development in both the chick and zebrafish. Further characteriza tion will provide insight into the roles of members of the FKHR subfamily o f forkhead-related genes during both normal and neoplastic development.