Epiregulin is a member of the epidermal growth factor (EGF) family, and has certain characteristics that are di erent from that of EGF, including mitogenic responses and binding to EGF receptor (EGFR). Epiregulin may also have another cell surface receptor and/or induces di erent receptor heterodimerizations for intracellular signaling. We investigated the binding ability of epiregulin to four ErbB family receptors using four human breast carcinoma cell lines that expressed di erent subsets of receptors. Chemical cross-linking experiments showed that [ 125 I]epiregulin directly bound to each of EGFR and ErbB-4 but not to ErbB-2 and ErbB-3. Furthermore, although epiregulin stimulated tyrosine phosphorylation of all four ErbB receptors, the main intracellular signal was mediated by ErbB-4 and/or EGFR. The pattern of activation of ErbB family receptors was di erent from that of other EGF-related ligands. Our ®ndings indicate that ErbB-4 and EGFR are receptors for epiregulin, and suggest that EGFrelated ligands transduce signals for di erent biological responses by the hierarchical mechanism.

Rev i ew o f P ri m a ry P r eve n t i o n o fTy p e 2 D i a b ete s i n We s te rn Au s t r a l i a E xe c u t i ve S u m m a ry R E V I E W O F P R I M A RY P R E V E N T I O N O F T Y P E 2 D I A B E T E S I N W E S T E R N A U S T R A L I R E V I E W O F P R I M A RY P R E V E

We have recently identified epiregulin as a new growth regulator and a member of the epidermal growth factor (EGF) family. Epiregulin has certain characteristics that are different from those of the classical members of the EGF family, EGF and transforming growth factor alpha, including mitogenic responses on several normal cells and binding to EGF receptors on epidermoid carcinoma A431 cells. In the present study we cloned and identified the expression of human epiregulin transcript. The human epiregulin gene encoded a 163-residue putative transmembrane precursor containing an EGF-like domain in the internal segment, and the structural organization was similar to that of other members of the EGF family that bind to EGF receptors. Northern blot analysis showed the expression of human epiregulin to be mainly on peripheral blood macrophages and the placenta in normal tissues, and was highest on epithelial tumour cell lines in various types of tumour cell lines. The expression profile was quite different from that of other members of the EGF family in normal and tumour cells. Recombinant expression in mammalian cells also showed that human epiregulin was secreted as a soluble form of approx. 5 kDa that is biologically active on the basis of the stimulation of DNA synthesis. Our findings suggest that epiregulin is involved in certain physiological processes such as maintenance or development of normal cell growth, and the progression of carcinomas.

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During the course of our screening program for natural product drugs effective against multidrug resistant cells by using adriamycin resistant HL-60 cells, we have discovered a new 12 membered macrolide FD-895 in the fermentation broth of Streptomyces hygroscopicus A-9561 isolated from a soil sample collected at Iriomote Island, Okinawa prefecture, Japan. FD-895 showed stronger cytocidal activities against in vitro tumor cell lines than adriamycin. FD-895 had the same IC50values against parent and adriamycin resistant HL-60 cells.A major drawback to cancer chemotherapy is that many tumors are either intrinsically resistant to the compoundor develop resistance over the course of treatment. Treatment with chemotherapeutic agents generally results only in temporary remission of tumor disease in the clinic.It is also well knownexperimentally1 '2) that mammalian cells selected for resistance to a single cytotoxic natural product drug can becomenot only resistant to the agent used but also cross-resistant to a wide range of structurally and functionally unrelated antibiotics and alkaloids. For these reasons the developmentof chemotherapeutic agents equally effective against malignant and resistant cells has been desired world wide for overcoming tumor disease. From this standpoint, we have explored natural product drugs effective against multidrug resistant cells.In the course of our screening program using adriamycin resistant HL-60cells to discover low molecular compoundsproduced in microbial fermentation broths and capable of circumventing multidrug resistance, we have discovered a new 12-membered macrolide FD-895 (Fig. 1)

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Mushroom fruiting, the reproduction of fungi, has broad implications for forest health, terrestrial biomass turnover, and global carbon cycle. However, little is known about the difference in phenology and environmental drivers of mushroom fruiting between functional guilds, e.g., ectomycorrhizal (ECM) mutualists and saprotrophs (SAP). There is a remarkable difference between ECM and SAP fungi in their available carbon sources and lifecycles, and thus these fungal groups are likely to differ in fruiting phenology. We analyzed intra- and inter-annual phenological patterns of mushroom fruiting throughout the year using a long-term census dataset of mushroom-forming fungi in a Japanese oak forest in which a total of 11,923 mushroom counts (668 species) were recorded during monthly intervals from 1982 to 2011. ECM fungi showed a unimodal seasonal fruiting peak from mid-summer to early autumn; litter-decomposing fungi showed moderate fruiting peaks from early summer or early autumn, and the phenology of wood-decomposing fungi varied considerably among the genera. Each functional group was controlled by a different set of external factors; temperature and rainfall increased ECM fungal fruiting, but key factors substantially differed among the genera of litter- and wood-decomposing fungi in taxon-specific ways. Our results suggest that fungal fruiting phenology may be affected by the seasonality of carbohydrate availability. The highly scheduled reproduction of ECM fungi may reflect temperature-dependent increases and drought-induced decreases of photosynthetic activity in host plants rather than improved growth conditions for fungi during the summer. We argue that the way a fungus obtains carbohydrates may explain a substantial fraction of the fruiting phenology, which may make a differential contribution to the community structure of fungus-associated organisms and terrestrial biomass turnover based on fungal functional groups.