Notebook

Contents Id and angio Testosterone boost to favored offspring More dopamine To B or not to B Mice that know when to say when Viral conquest Unraveling helicase Done in by a sucker ID AND ANGIO When Robert Benezra of the Memorial Sloan-Kettering Cancer Center, New York, and colleagues knocked out two proteins that inhibit transcription factors in mice, they expected to see premature neural differentiation. In addition, however, they noticed that the absence of those two proteins, Id1 and Id3, disrupted angiogenesis in the central nervous system (D. Lyden et al., "Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumor xenografts," Nature, 401:670-7, Oct. 14, 1999). "That was a surprise to us." Benezra notes that the two proteins could prove to be important anticancer targets because Id knockouts in tumor xenograft models showed "absolutely zero potential" to grow breast and lymphoma tumors. "We do already have a small-molecule lead, which interacts and, we think, inhibits this protein," Benezra comments. Benezra is excited about targeting Id1 and Id3 because those proteins are upregulated in tumor cells but are rarely expressed in adult tissue. --Paul Smaglik ANGIOGENESIS TARGET: Memorial Sloan-Kettering Cancer Center researchers show that proteins necessary to form branching and sprouting blood vessels within tumors (left) were present in mice that had all four copies of the Id genes, but they were missing in those lacking three of the four gene copies, resulting in poor blood-vessel growth (right). TESTOSTERONE BOOST TO FAVORED OFFSPRING Offspring of highly ornamental males tend to beat their siblings in the survival stakes--in birds at least. Experiments reveal a new twist to the old idea that these offspring either are blessed with better genes or receive a disproportionate share of maternal care--females secrete more testosterone into yolks after mating with the avian version of sexy males (D. Gil et al, "Male attractiveness and differential testosterone investment in zebra finch eggs," Science, 286:126-8, Oct. 1, 1999.). Female zebra finches were mated to males with either red bands or green bands on their legs. Apparently the ladies went for the red. "Each female had two clutches with a different male in each of them, and we compared the difference between clutches for the same females," notes Diego Gil, a University of Paris postdoc. Chicks of red-banded males enjoyed the benefits of high testosterone, but not the chicks of green-banded males. And testosterone level can make a big difference in young birds' lives, providing strength and stamina that enable them to outcompete less manly nestmates. How the female controls testosterone production and secretion remains unknown. "My hunch is that she is responding to a higher degree of stimulation by the male, but options are open," speculates Gil. "It could also be that males are manipulating females by their behavior."--Ricki Lewis MORE DOPAMINE The "dopamine hypothesis," that effective antipsychotics work by blocking dopamine neurotransmission, has been shaken in recent years. "Atypical" antipsychotic drugs have demonstrated effectiveness despite relatively low dopamine inhibition in the brain compared to the earlier, "classical," neuroleptics. But new Swedish research now appears to have floored the hypothesis by showing that enhancing dopamine transmission in the cortical areas while further reducing its overall inhibition in the brain improves antipsychotic effects (P. Hertel et al., "Enhanced cortical dopamine output and antipsychoticlike effects of raclopride by alpha-2 adrenoceptor blockade," Science, 286:105-7, Oct. 1, 1999). A team led by senior author Torgny Svensson, a pharmacology professor at Karolinska Institute in Stockholm, drew on previous work showing that the atypical antipsychotic clozapine (Clozaril, Novartis) markedly enhances cortical dopamine output, and that schizophrenia may be associated with impaired dopamine function in the prefrontal cortex, from which cognitive functioning and goal-oriented behavior arise. The researchers mimicked and enhanced the effects of clozapine in a standard rat model by combining two blocking agents. Raclopride inhibits dopamine and idazoxan binds another receptor, adrenoceptor alpha-2, which ultimately increases dopamine output in the prefrontal cortex. Their results indicate that clozapine "may not at all be optimally designed," Svensson declares. "Thus, we can hope for even better drugs in coming years, with [far fewer] side effects."--Steve Bunk TO B OR NOT TO B In the absence of either E2A gene or the early B-cell factor, B-cell development is aborted at the earliest stages. Meinrad Busslinger and colleagues at the Research Institute of Molecular Pathology, Vienna, Austria, have identified a third transcription factor that is critical for B-lineage commitment: the B-cell-specific activator protein encoded by the Pax5 gene (S.L. Nutt et al., "Commitment to the B-lymphoid lineage depends on the transcription factor Pax5," Nature, 401:556-62, Oct. 7, 1999). When the Pax5 gene is inactivated, B-lymphoid cells arrest in the pro-B cell development stage. In vitro Pax5-deficient pro-B cells possess a broad developmental potential similar to hematopoietic stem cells and can develop into macrophages, osteoclasts, dendritic cells, granulocytes, and natural killer cells, depending on specific cytokines present. This finding may have practical applications for immunology research, since B cells can efficiently reconstitute the thymus and regenerate the entire T-lymphoid system in mice whose B-cell pathway has been blocked (A.G. Rolink et al., "Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell progenitors," Nature, 401:603-6, Oct. 7, 1999). "[Researchers] can use retroviruses to infect Pax5-deficient pro-B cells and modify [the cells] with foreign genes that may influence T-cell development," explains Busslinger. This technique may offer an alternative to tedious experiments involving transgenic mice. --Nadia S. Halim MICE THAT KNOW WHEN TO SAY WHEN By learning why a strain of transgenic mice chooses to stay sober, researchers may have inched closer to developing better pharmaceuticals for treating drug addiction. Scientists have long known that alcohol enhances the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). But studies have yielded contradictory results as to exactly how ethanol activates GABA receptors (called GABA A receptors) to do so. It's also known that protein kinases can alter GABA A sensitivity to alcohol--but results are mixed as to whether their effects are stimulatory or inhibitory. Scientists at the Alcohol Research Center at the University of California, San Francisco, sought to clarify these interactions by studying protein kinase C* (PKC*), an enzyme that had previously demonstrated increased alcohol-induced activity in neuronal cells. They found that genetically engineered mice missing the gene for PKC* had an increased sensitivity for ethanol and a resulting 75 percent reduction in alcohol preference versus control mice. (C.W. Hodge et al., "Supersensitivity to allosteric GABA A receptor modulators and alcohol in mice lacking PKC*," Nature Neuroscience, 2:997-1002, November 1999). As for the biochemical underpinnings of the effect, researchers found that the mice were less sensitive to direct GABA activation than they were to allosteric GABA A activation, the sort that can only occur with the help of other compounds--sedatives like valium that are often used to treat anxiety or epilepsy. This suggests that therapies that block PKC* may not only hold promise for treating alcohol abuse, but for treating these conditions as well--without the negative addictive side effects of sedatives. Says lead author Clyde Hodge, an assistant professor of neurology at UC-San Francisco: "It could be an indirect way into that system."--Eugene Russo VIRAL CONQUEST Conquering without killing--this strategy ensures that a virus can replicate and infect other cells. Allan S. Lau and colleagues at the University of California, San Francisco, have developed a model that shows a virus can establish a persistent infection if it can surmount apoptosis, an important host defense (M.C. Yeung et al., "Inhibitory role of the host apoptogenic gene PKR in the establishment of persistent infection by encephalomyocarditis virus in U937 cells," Proceedings of the National Academy of Sciences, 96:11860-5, Oct. 12, 1999.) The PKR gene produces a protein kinase that triggers apoptosis in response to double-stranded RNA, a sign of viral invasion. "When cells with PKR suppressed are exposed to encephalomyocarditis virus (EMCV), we saw something quite unexpected," says Lau. Instead of killing the cells, the virus established a persistent infection. The infected cells continued to grow at a slower rate and pumped out virions. Also, over time the virus became less infectious. This model may be useful in studying how other viruses such as hepatitis and HIV establish persistent infections. In the future, a drug that activates PKR could be developed for use in combination therapy. --Nadia S. Halim UNRAVELING HELICASE X-ray crystallography has provided a Harvard Medical School team with a high-resolution snapshot of a DNA helicase, the motor that unwinds double-stranded DNA prior to replication. The protein zips along the lagging strand of the replication fork, separating the two DNA strands so they can be copied by a DNA polymerase, notes senior author Tom Ellenberger, a Harvard structural biologist (M.R. Sawaya et al., "Crystal structure of the helicase domain from the replicative helicase-primase of bacteriophage T7," Cell, 99:167-77, Oct. 15, 1999). "We're interested in what drives the motor along one strand--why it moves in one direction and how it moves so quickly," Ellenberger comments. The crystal structure, which reveals nucleotide cofactors bound in crevices between the six subunits of this donut-shaped molecule, supplies some clues. Helicase-catalyzed DNA unwinding probably involves a reciprocating motion within the protein ring that causes the protein to inchworm or ratchet along the DNA, Ellenberger hypothesizes. The structure shows how the cleavage of high-energy nucleotide cofactors could be coupled with the proposed conformational changes. Additional helicase structures may reveal different conformations of the ring as it interacts with a DNA substrate. "Some of that work is under way," Ellenberger concludes. --Paul Smaglik DONE IN BY A SUCKER DNA fingerprinting usually snags rapists who leave sperm, blood, skin, or hair at crime scenes. For one would-be rapist in Israel, a forgotten lollipop led to his confession. The man entered the victim's home on March 16, 1997. She fought off the sexual assault, but he hit her over the head, rendering her unconscious and unable to see him. Forensic scientists at the Israel National Police Headquarters in Jerusalem obtained eyeglasses from the crime scene, surveyed opticians for the brand, then checked police records and found a mug shot of a man wearing the same peculiar frames. The glasses would ultimately prove unsuitable for DNA analysis because the police officers had tried them on, while joking around. They had more success with a half-eaten lollipop found annealed to the bloody sheet. Forensic experts obtained DNA from the victim's blood and from the suspect's saliva, which they got from the lollipop's base. Uzi Motro, a professor of statistics from the Hebrew University of Jerusalem, calculated that one out of every 480 people in the population could have left that particular DNA on the lollipop (C. Oz et al, "Forensic identification of a rapist using unusual evidence," The Journal of Forensic Sciences, 44:860-2, September 1999). The suspect confessed when presented with this evidence. --Ricki Lewis

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