The intricate role of Smads in the regulation of FPGS gene expression

摘要: Antifolates are important components of treatment regimens hematological malignancies and solid tumors. Following cellular uptake, antifolates undergo polyglutamylation, catalyzed by the enzyme folylpoly-γ-glutamate synthetase (FPGS), which is crucial for their intracellular retention cytotoxic activity. Hence, loss FPGS activity results in diminished antifolate polyglutamylation resistance. Aberrant TGF-β/Smad signaling thought to be a major contributor leukemogenesis, as members this pathway negative regulators hematopoiesis. Recently we characterized human resistant leukemia cell line MTA C-3 lost 97% its harbors heterozygous point mutation exon12 FPGS. This resulted 99% expression wild type allele, while mutant allele was retained. Research into molecular mechanism underlying selective silencing these cells established an intragenic transcriptional regulator, with ability drive transcription vitro . We further showed that can occupied many factors chromatin remodeling proteins (e.g. Smad4/Ets-1, HP-1 Brg1) vivo inversely correlated binding Smad4/Ets-1 complex exon12, both acute lymphoblastic myeloid blast specimens. Here demonstrate possible roles Smads regulation gene expression. found 5-aza-deoxycytidine trichostatin A repression well decreased drug sensitive parental CCRF-CEM cells. increased Smad3 inhibitory Smad7. These findings bear implications rational overcoming resistance leukemia.