Kelsi L. Kretschmann

Previous studies have revealed many parallels in the cell cycle regulation of the Ace2 and Swi5 transcription factors. Although both proteins begin entry into the nucleus near the start of mitosis, here we show that Ace2 accumulates in the nucleus and binds DNA about 10 min later in the cell cycle than Swi5. We used chimeric fusions to identify the N-terminal region of Ace2 as responsible for the delay, and this same region of Ace2 was required for interaction with Cbk1, a kinase necessary for both transcriptional activation by Ace2 and asymmetric distribution of Ace2. Ace2 and Swi5 also showed differences in prevalence during the cell cycle. Swi5 is apparently degraded soon after nuclear entry, whereas constant Ace2 levels throughout the cell cycle suggest Ace2 is exported from the nucleus. Our work suggests that the precise timing of Ace2 accumulation in the nucleus involves both a nuclear export sequence and a nuclear localization signal, whose activities are regulated by phosphorylation.

Macrophage Stimulating Protein (MSP) is the only known ligand for the receptor tyrosine kinase Ron. The MSP/Ron pathway is involved in several important biological processes, including macrophage activity, wound healing, and epithelial cell behavior. A role for MSP/Ron in breast cancer has recently been elucidated, wherein this pathway regulates tumor growth, angiogenesis, and metastasis. Here, we review the recent literature surrounding MSP/Ron function in tumor cells, inflammatory cells, and osteoclasts - cell types that often coexist in breast tumor microenvironments. We discuss the potential implications of MSP/Ron activity occurring concurrently in these cell types on tumor progression and metastasis. Lastly, we outline the potential for targeting MSP/Ron as a novel therapy for breast cancer, and for other cancer types.