Inhibition of the mammalian transcription factor LSF induces S-phase-dependent apoptosis by downregulating thymidylate synthase expression
AUTOR(ES)
Powell, Christina M.H.
FONTE
Oxford University Press
RESUMO
The thymidylate synthase (TS) gene, which is induced at the G1–S transition in growth-stimulated cells, encodes an enzyme that is essential for DNA replication and cell survival. Here we demonstrate that LSF (LBP-1c, CP2) binds to sites within the TS promoter and intronic regions that are required for this induction. Mutation of the LSF binding sites inhibits G1–S induction of mRNA derived from a TS minigene. Furthermore, expression of dominant-negative LSF (LSFdn) prevents the increase in TS enzyme levels during G1–S, and induces apoptosis in growth- stimulated mouse and human cell lines. Such apoptosis can be prevented either by circumventing the TS requirement through addition of low concentrations of thymidine, or by coexpression of the TS gene driven by a heterologous promoter. Induction of apoptosis by LSFdn parallels the process known as thymineless death, which is induced by the TS inhibitor and chemotherapeutic drug 5-fluorodeoxyuridine. Thus, LSF is a novel regulatory factor that supports progression through S-phase by targeting a single gene that is critical for cell survival.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=302058Documentos Relacionados
- S-phase-dependent cell cycle disturbances caused by Aleutian mink disease parvovirus.
- Cell cycle-dependent expression of thymidylate synthase in Saccharomyces cerevisiae.
- Splicing signals are required for S-phase regulation of the mouse thymidylate synthase gene.
- Estrogen-induced apoptosis by inhibition of the erythroid transcription factor GATA-1.
- Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.