Colorectal cancer (CRC) results from the progressive accumulation of both genetic and epigenetic alterations that lead to the transformation of normal colorectal epithelium to benign (adenoma) and invasive (carcinoma) disease. Since its discovery in mutated form as the causative gene for familial adenomatous polyposis coli (FAP), as well as in many sporadic CRCs, the APC tumor suppressor has been shown to possess numerous functions within the cell including regulation of WNT signaling pathways and its transcriptional effects, cell migration, and chromosome separation. In recent years, other novel roles for APC have been investigated and suggest that APC can also repress DNA replication and enhance apoptosis.
View Article and Find Full Text PDFCells deficient in the recQ-like helicase BLM are characterized by chromosome changes that suggest the disruption of normal mechanisms needed to resolve recombination intermediates and to maintain chromosome stability. Human BLM and topoisomerase IIα interact directly via amino acids 489-587 of BLM and colocalize predominantly in late G2 and M phases of the cell cycle. Deletion of this region does not affect the inherent in vitro helicase activity of BLM but inhibits the topoisomerase IIα-dependent enhancement of its activity, based on the analysis of specific DNA substrates that represent some recombination intermediates.
View Article and Find Full Text PDFBackground & Aims: The adenomatous polyposis cell (APC) tumor suppressor is a multifunctional protein involved in cell migration, proliferation, differentiation, and apoptosis. Cleavage of APC and the subsequent release of an amino-terminal segment are necessary for a transcription-independent mechanism of APC-mediated apoptosis. The aim of the current study is to elucidate the mechanism by which the amino-terminus of APC contributes to the enhancement of apoptosis.
View Article and Find Full Text PDFGenotoxic stress triggers a rapid translocation of p53 to the mitochondria, contributing to apoptosis in a transcription-independent manner. Using immunopurification protocols and mass spectrometry, we previously identified the proapoptotic protein BAK as a mitochondrial p53-binding protein and showed that recombinant p53 directly binds to BAK and can induce its oligomerization, leading to cytochrome c release. In this work we describe a combination of molecular modeling, electrostatic analysis, and site-directed mutagenesis to define contact residues between BAK and p53.
View Article and Find Full Text PDFThe mitochondrial folate transporter (MFT) was previously identified in human and hamster cells. Sequence homology of this protein with the inner mitochondrial membrane transporters suggested a domain structure in which the N- and C-termini of the protein are located on the mitochondrial intermembrane-facing surface, with six membrane-spanning regions interspersed by two intermembrane loops and three matrix-facing loops. We now report the functional significance of insertion of the c-myc epitope into the intermembrane loops and of a series of site-directed mutations at hamster MFT residues highly conserved in orthologues.
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