Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis

Introduction Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARγ and RARα/β in favor of RARγ. Methods The effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium, mammary tumor cells obtained from the MMTV-Myc transgenic mouse model as well as human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RARα-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the MMTV-Myc mouse model of mammary tumorigenesis. Results Modulation of the RARα/β to RARγ expression in mammary glands of normal mice, oncomice, and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation, survival and tumor growth. Treatment of MMTV-Myc mice with the RARα-selective agonist Am580 led to significant inhibition of mammary tumor growth (~90%, P\u3c0.001), lung metastasis (P\u3c0.01) and extended tumor latency in 63% of mice. Immunocytochemical analysis showed that in these mice, RARα responsive genes such as Cyp26A1, E-cadherin, cellular retinol-binding protein 1 (CRBP1) and p27, were up-regulated. In contrast, the mammary gland tumors of mice that responded poorly to Am580 treatment (37%) expressed significantly higher levels of RARγ. In vitro experiments indicated that the rise in RARγ was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RARα pathway is linked to tumor growth inhibition, differentiation and cell death. Conclusions The functional consequence of the interplay between c-Myc oncogene expression and the RARγ to RARα/β balance suggests that prevalence of RARγ over-RARα/β expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARα-isotype-specific agonists and warrant monitoring during clinical trials. See related editorial by Garattini et al http://breast-cancer-research.com/content/14/5/11

The Miocene – Pliocene boundary and the Messinian Salinity Crisis in the easternmost Mediterranean: insights from the Hatay Graben (Southern Turkey).

The Hatay Graben is one of three easternmost basins in the Mediterranean that preserve sediments that span the Miocene-Pliocene boundary, including gypsums from the Messinian Salinity Crisis (MSC). Here we integrate existing data and present new sedimentological and micropalaeontological data to investigate the palaeoenvironments of late Miocene to early Pliocene deposits and place this important area into a regional stratigraphic framework. Six sections are described along a ~ W – E transect illustrating the key features of this time period. Late Miocene (Pre-MSC) sediments are characterised by open marine marls with a benthic foraminiferal fauna suggestive of water depths of 100 – 200 m or less. Primary lower gypsum deposits are determined to be absent from the graben as sedimentological and strontium isotopes are characteristic of the resedimented lower gypsums. The intervening Messinian erosion surface is preserved near the basin margins as an unconformity but appears to be a correlative conformity in the basin depocentre. No Upper Gypsums or ‘Lago–Mare’ facies have been identified but available data do tentatively suggest a return to marine conditions in the basin prior to the Zanclean boundary. Sediments stratigraphically overlying the Messinian gypsums and marls are coarse-grained sandstones from coastal and Gilbert-type delta depositional environments. The Hatay Graben is not only strikingly similar to Messinian basins on nearby Cyprus but also to the overall model for the MSC, demonstrating the remarkable consistency of palaeoenvironments found in marginal basins across the region at this time

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters

Microbial Biotechnolog

Regulation of mTORC1 and mTORC2 Complex Assembly by Phosphatidic Acid: Competition with Rapamycin▿

mTOR, the mammalian target of rapamycin, is a critical node for control of cell growth and survival and has widely been implicated in cancer survival signals. mTOR exists in two complexes: mTORC1 and mTORC2. Phospholipase D (PLD) and its metabolite phosphatidic acid (PA) have been implicated in the regulation of mTOR; however, their role has been controversial. We report here that suppression of PLD prevents phosphorylation of the mTORC1 substrate S6 kinase (S6K) at Thr389 and the mTORC2 substrate Akt at Ser473. Suppression of PLD also blocked insulin-stimulated Akt phosphorylation at Ser473 and the mTORC2-dependent phosphorylation of PRAS40. Importantly, PA was required for the association of mTOR with Raptor to form mTORC1 and that of mTOR with Rictor to form mTORC2. The effect of PA was competitive with rapamycin—with much higher concentrations of rapamycin needed to compete with the PA-mTORC2 interaction than with PA-mTORC1. Suppressing PA production substantially increased the sensitivity of mTORC2 to rapamycin. Data provided here demonstrate a PA requirement for the stabilization of both mTORC1 and mTORC2 complexes and reveal a mechanism for the inhibitory effect of rapamycin on mTOR. This study also suggests that by suppressing PLD activity, mTORC2 could be targeted therapeutically with rapamycin