The transcription factor FOXM1 (Forkhead box M1): proliferation-specific expression, transcription factor function, target genes, mouse models, and normal biological roles

Abstract

FOXM1 (Forkhead box M1) is a typical proliferation-associated transcription factor, which stimulates cell proliferation and exhibits a proliferation-specific expression pattern. Accordingly, both the expression and the transcriptional activity of FOXM1 are increased by proliferation signals, but decreased by antiproliferation signals, including the positive and negative regulation by protooncoproteins or tumor suppressors, respectively. FOXM1 stimulates cell cycle progression by promoting the entry into S-phase and M-phase. Moreover, FOXM1 is required for proper execution of mitosis. Accordingly, FOXM1 regulates the expression of genes, whose products control G1/S-transition, S-phase progression, G2/M-transition, and M-phase progression. Additionally, FOXM1 target genes encode proteins with functions in the execution of DNA replication and mitosis. FOXM1 is a transcriptional activator with a forkhead domain as DNA binding domain and with a very strong acidic transactivation domain. However, wild-type FOXM1 is (almost) inactive because the transactivation domain is repressed by three inhibitory domains. Inactive FOXM1 can be converted into a very potent transactivator by activating signals, which release the transactivation domain from its inhibition by the inhibitory domains. FOXM1 is essential for embryonic development and the foxm1 knockout is embryonically lethal. In adults, FOXM1 is important for tissue repair after injury. FOXM1 prevents premature senescence and interferes with contact inhibition. FOXM1 plays a role for maintenance of stem cell pluripotency and for self-renewal capacity of stem cells. The functions of FOXM1 in prevention of polyploidy and aneuploidy and in homologous recombination repair of DNA-double-strand breaks suggest an importance of FOXM1 for the maintenance of genomic stability and chromosomal integrity.