Retinoblastoma pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase-promoting complex.

ABSTRACT: We have examined the mechanism of normal DNA methyltransferase 1 (DNMT1) degradation as well as its mechanism of dysregulation in cancer. We have previously reported that DNMT1 protein levels were elevated and abnormally stabilized because of defective degradation through its N-terminal destruction domain. Here, we report that DNMT1 was abnormally stabilized in several cancer cell lines and that, in cells with normal DNMT1 destruction, depletion of CDC20 or FZR1 (two substrate recognition adaptor components of the anaphase-promoting complex) resulted in stabilization of DNMT1 that was partially dependent on the N-terminal destruction domain, thus implicating this cell cycle regulator in the destruction of DNMT1. MAD2, an inhibitor of CDC20, was shown to stabilize DNMT1 levels, and overexpr

SUBMITTER: Agoston AT 

PROVIDER: S-EPMC1854953 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature