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Nature Research Journals press release

May 15, 2005

[1] Molecule that induces tumour regression

DOI: 10.1038/nature03579

A promising approach to eliminate cancer cells is to trigger cell death (apoptosis) with inhibitors that bind to and block anti-apoptotic proteins that help keep cancer cells alive - as reported in an advanced online publication in Nature. A newly discovered small-molecule inhibitor, called ABT-737, interferes with anti-apoptotic proteins to kill certain cancer cells directly and greatly enhance the effectiveness of chemotherapy, say the researchers.

Proteins that inhibit apoptosis, such as Bcl-XL, Bcl-2, and Bcl-w, play a role in tumour formation, growth and resistance to treatment. Stephen Fesik and colleagues used a sophisticated nuclear-magnetic-resonance-based method of identifying lead compounds to screen a library of chemicals, isolate a promising small molecule and modify it to produce ABT-737. The inhibitor binds to these anti-apoptotic proteins with an affinity two to three orders of magnitude greater than any previously reported molecule.

ABT-737 alone was found to effectively kill certain cancer cell lines, including lymphoma and small-cell lung carcinoma (SCLC) lines, and to enhance the effects of chemotherapy and radiation on other cancer cell lines. Importantly, in a mouse model, ABT-737 by itself caused complete regression of human SCLC tumour xenografts.

Author contact:
Stephen Fesik (Abbott Laboratories, Abbott Park, IL, USA)
Tel: +1 847 937 1201, E-mail: Stephen.Fesik@abbott.com



***********************************************NATURE MATERIALS*************************************
(http://www.nature.com/naturematerials)

[2] Stiff handling of genes

DOI: 10.1038/nmat1392

The potential of materials for enhancing gene delivery into cells may be determined more by their stiffness than by their chemical properties, according to new research published in the June issue of Nature Materials.

Current efforts to improve the delivery efficiency of non-viral gene vectors or carriers are focused on manipulations of the vector itself, whereas the influence of environmental factors is too often ignored. The results obtained by David Mooney and colleagues suggest that, when it comes to gene transfer and expression, cells may care less about surface chemistry and more about the mechanical properties of the substrate to which they are attached.

An extensive study of several biomaterials used for cell cultures shows that mechanical factors, such as the rigidity of the substrate, regulate the cell's ability to uptake and express genes from non-viral carriers. Cells attached to more rigid surfaces uptake more condensed DNA complexes and ultimately express more of the transferred gene. This surprising revelation suggests that stiffness is a general material-based point of control for non-viral gene delivery that may have implications for the development of biomaterials for localized gene therapy, say the researchers.

Author contact:
David Mooney Harvard University, Cambridge, MA, USA)
Tel: +1 617 384 9624, E-mail: mooneyd@deas.harvard.edu


Other papers from Nature Materials to be published online at the same time and with the same embargo:

[3] Pressure-induced ferromagnetism in (In,Mn)Sb dilute magnetic semiconductor
DOI: 10.1038/nmat1388

[4] Nanowire dye-sensitized solar cells
DOI: 10.1038/nmat1387

[5] Inverse magnetocaloric effect in ferromagnetic Ni-Mn-Sn alloys
DOI: 10.1038/nmat1395

[6] Biomaterials functionalization using a novel peptide that selectively binds to a conducting polymer
DOI: 10.1038/nmat1397

[7] Shape-memory nanoparticles from inherently non-spherical polymer colloids
DOI: 10.1038/nmat1389


*******************************************NATURE NEUROSCIENCE ***********************************
(http://www.nature.com/natureneuroscience)

[8] Brain changes over the menstrual cycle

DOI: 10.1038/nn1469

Hormonal fluctuations over the course of the menstrual (or estrus) cycle can have noticeable effects on the brain and behavior. During different phases of the cycle, neurons express different subtypes of the receptor for the inhibitory neurotransmitter GABA, as reported in the June issue of Nature Neuroscience, which may provide a molecular basis for some of these changes.

Up to 78% of epileptic women have more seizures during the phase when progesterone declines, a condition called catamenial epilepsy. Five percent of menstruating women have premenstrual dysphoric disorder or PMDD, and routinely experience severe anxiety and depression in the week or so before menstruation. Estrogen and progesterone affect both excitatory and inhibitory signaling in the brain, but the mechanisms behind these changes in seizure susceptibility and anxiety were unknown.

In mice, Istvan Mody and colleagues found that neurons in the hippocampus -- a brain region important in seizure generation -- expressed more of a particular subtype of inhibitory GABA receptors during the phase of the cycle when progesterone levels are low. This caused a dramatic reduction in so-called 'tonic' or persistent inhibition of neural signaling, along with corresponding increases in seizure susceptibility and anxiety.

In the high-progesterone phase of the cycle, the authors found the opposite pattern: expression of this subtype of GABA receptors was higher, tonic inhibition was increased, and seizure susceptibility was reduced. Thus the authors suggest that these GABA receptor changes may be responsible for the effects of the menstrual cycle on seizure and anxiety levels seen in catamenial epilepsy and PMDD.

Author contact:
Istvan Mody (University of California at Los Angeles School of Medicine, CA, USA)
Tel: +1 310 206 4481; E-mail: mody@ucla.edu

Additional contact for comment on paper:
Kevin Staley (University of Colorado Health Sciences Center, Denver, CO, USA)
Tel: +1 303 315 5679, E-mail: Kevin.Staley@UCHSC.edu


Other papers from Nature Neuroscience to be published online at the same time and with the same embargo:

[9] ATP mediates rapid microglial response to local brain injury in vivo
DOI: 10.1038/nn1472

[10] LINGO-1 negatively regulates myelination by oligodendrocytes
DOI: 10.1038/nn1460

[11] RNA editing produces glycine receptor alpha3P185L, resulting in high agonist potency
DOI: 10.1038/nn1467

[12] Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses
DOI: 10.1038/nn1468


*******************************************NATURE CELL BIOLOGY ************************************
(http://www.nature.com/naturecellbiology)

[13] Fat: the big picture

DOI: 10.1038/ncb1259

The network of genes required for early steps in the development of brown fat cells has been identified in new research to be published in the June issue of Nature Cell Biology, further substantiating the link between insulin signalling and control of fat cells. The complete picture of the network should provide an important blueprint for future clinical and therapeutic approaches to diabetes and obesity.

Mice defective in different aspects of insulin signalling - a process known to regulate fat-cell differentiation - produce precursors at varying stages of fat-cell differentiation. These precursors were used to identify the global pattern of gene expression as cells develop into fully defined brown fat cells. Ronald Kahn and colleagues identified 374 genes in total. The network includes newly identified genes important for kicking off the differentiation process, as well as those previously known to be involved in the final stages.

Necdin, one of the key factors identified in the study, is an inhibitor of the process and loss of its expression is essential for these fat cells to develop properly. In fact, forced loss of Necdin expression can re-activate the development process in prematurely blocked immature fat cells. Necdin is an entirely unkno

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