The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future. © 2014 Adam et al

The role and regulation of D-type cyclins in the plant cell cycle

The G1 phase of the cell cycle represents a period of commitment to cell division, both for cells stimulated to resume division from a resting or quiescent state, and for cells involved in repeated cell cycles. During this period, various signals that affect the cells ’ ability to divide must be assessed and integrated. G1 culminates in the entry of cells into S phase, when DNA replication occurs. In addition, it is likely that several types of differentiation decision may be taken by cells in the G1 phase. In both animals and plants, it appears that D-type cyclins play an important role in the cell cycle responses to external signals, by forming the regulatory subunit of cyclin-dependent kinase complexes. The phosphorylation targets of D-cyclin kinases in mammalian cells are the retinoblastoma (Rb) protein and close relatives. Unphosphorylated Rb can associate with E2F transcription factors, preventing transcription of genes under E2F control until the G1/S boundary is reached. The conservation of Rb and E2F proteins in plants suggests that this pathway is therefore conserved in all higher eukaryotes, although it is absent in fungi and yeasts. Here we review the current understanding of the roles and regulations of D-type (CycD) cyclins in plants