Calcium transport and signaling in the mammary gland: Targets for breast cancer

The mammary gland is subjected to extensive calcium loads during lactation to support the requirements of milk calcium enrichment. Despite the indispensable nature of calcium homeostasis and signaling in regulating numerous biological functions, the mechanisms by which systemic calcium is transported into milk by the mammary gland are far from completely understood. Furthermore, the implications of calcium signaling in terms of reaulating proliferation, differentiation and apoptosis in the breast are currently uncertain. Deregulation of calcium homeostasis and signaling is associated with mammary gland pathophysiology and as such, calcium transporters, channels and binding proteins represent potential drug targets for the treatment of breast cancer. (c) 2005 Elsevier B.V. All rights reserved.

Cyclic MrIA: A stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter

Conotoxins, disulfide-rich peptides from the venom of cone snails, have created much excitement over recent years due to their potency and specificity for ion channels and their therapeutic potential. One recently identified conotoxin, MrIA, a 13-residue member of the chi-conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. In the current study, we show that the, beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET. Furthermore, the cyclic version has increased resistance to trypsin digestion relative to the native peptide, an intriguing result because the cleavage site for the trypsin is not close to the cyclization site. The use of peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular disulfide-rich peptides.

The effect of manipulations to target contrast on emmetropization in chick

Emmetropization is dependent on visual feedback and presumably some measure of the optical and image quality of the eye. We investigated the effect of simple alterations to image contrast on eye growth and refractive development. A 1.6 cyc/deg square-wave-grating target was located at the end of a 3.3 cm cone,, imaged by a +30 D lens and applied monocularly to the eyes of 8-day-old chicks. Eleven different contrast targets were tested: 95, 67, 47.5, 33.5, 24, 17, 12, 8.5, 4.2, 2.1, and 0%. Refractive error (RE), vitreous chamber depth (VC) and axial length (AL) varied with the contrast of the image (RE diff. F-10.86 = 12.420, p < 0.0005; VC diff. F-10.86 = 8.756, p < 0.0005; AL diff. F-10.86 = 9.240, p < 0.0005). Target contrasts 4.2% and lower produced relative myopia (4.2%: RE diff = -7.48 +/- 2.26 D, p = 0.987; 2.1%: RE diff = -7.22 +/- 2.77 D, p = 0.951) of similar amount to that observed in response to a featureless 0% contrast target (RE diff = -9.11 +/- 4.68 D). For target contrast levels 47.5% and greater isometropia was maintained (95%: RE diff = 1.83 +/- 2.78 D; 67%: RE diff = 0.14 +/- 1.84 D; 47.5% RE diff = 0.25 +/- 1.82 D). Contrasts in between produced an intermediate amount of myopia (33.5%: RE diff = -2.81 +/- 1.80 D; 24%: RE diff = -3.45 +/- 1.64 D; 17%: RE diff = -3.19 +/- 1.54 D; 12%: RE diff = -4.08 +/- 3.56 D; 8.5%: RE diff = -4.09 +/- 3.60 D). We conclude that image contrast provides important visual information for the eye growth control system or that contrast must reach a threshold value for some other emmetropization signal to function. (c) 2005 Elsevier Ltd. All rights reserved.

Will diverse Tat interactions lead to novel antiretroviral drug targets?

More than fifteen years following the description of Tat as a critical HIV gene expression regulatory protein, additional roles for Tat in HIV replication have been described, including reverse transcription. Tat achieves function through direct interaction with viral proteins, including reverse transcriptase, and numerous cellular proteins including cyclin T1, RNA polymerase 11, protein kinase R (PKR), p300/CBP, and P/CAF. Despite our advanced knowledge of how Tat operates, this has not yet resulted in the discovery of effective agents capable of targeting various Tat functions. Nevertheless, Tat remains an attractive, virus-specific molecule and detailed understanding of specific protein interaction holds promise for future drug discovery.