👤 Michael P O'Hagan

Activation of the epithelial-to-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with colorectal cancer contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine-specific demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer and enhances cell migration. In this study, we determine that LSD1 expression is significantly elevated in patients with colorectal cancer with mutation of the catalytic subunit of PI3K, Show less

The mechanisms regulating nuclear export of proteins are not fully understood. To investigate whether the efficiency of protein nuclear export may depend on ongoing RNA synthesis and/or mRNA nuclear export, we used a microinjection approach with a fluorescent reporter protein containing a nuclear export signal (NES) and scored protein export in human fibroblasts under conditions when the synthesis or export of mRNAs was inhibited. We show that inhibition of transcription significantly attenuated generic NES-dependent nuclear export. Furthermore, digestion of endogenous nuclear RNAs by co-microinjection of RNAse A inhibited NES-dependent nuclear export. Finally, nuclear export of the NES reporter protein was significantly inhibited in cells in which nuclear export of mRNAs had been specifically blocked by microinjection of anti-TAP antibodies or by expression of a dominant negative form of NUP160. These results demonstrate a novel role for ongoing synthesis and export of mRNAs in NES-dependent protein nuclear export. Show less