Almost all polymerase II transcripts undergo alternative pre-mRNA splicing. Here, we review the functions of alternative splicing events that have been experimentally determined. The overall function of alternative splicing is to increase the diversity of mRNAs expressed from the genome. Alternative splicing changes proteins encoded by mRNAs, which has profound functional effects. Experimental analysis of these protein isoforms showed that alternative splicing regulates binding between proteins, between proteins and nucleic acids as well as between proteins and membranes. Alternative splicing regulates the localization of proteins, their enzymatic properties and their interaction with ligands. In most cases, changes caused by individual splicing isoforms are small. However, cells typically coordinate numerous changes in ‘splicing programs’, which can have strong effects on cell proliferation, cell survival and properties of the nervous system. Due to its widespread usage and molecular versatility, alternative splicing emerges as a central element in gene regulation that interferes with almost every biological function analyzed.

SUMMARY Metastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics, such as invasion, metastasis and stemness. To better understand the post-translational regulation of SNAIL, we performed a luciferase-based genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 which targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Serine-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of post-translational regulation of EMT and cancer metastasis.

SUMMARY The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis but its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells (MECs) under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. Finally, this functional significance of MTDH-SND1 interaction is supported by clinical analysis of human breast cancer samples.

Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.