In This Issue
CELL BIOLOGY
Pyrimidine-starved cells trigger p53
A tumor-suppressing protein known as p53 is activated when a cell suffers extensive DNA damage and either halts the cell cycle or triggers cell death. If a cell is starved for pyrimidine nucleotides—DNA's building blocks—p53 protects the cell by stalling its growth in the synthesis (S) phase. Exactly how p53 is activated during starvation, however, is not known. Kedar Hastak et al. report evidence, consistent with previous research, that suggests that when normal, healthy cells are deprived of pyrimidine nucleotides, the incorporation of incorrect deoxynucleotides into DNA activates mismatch-repair enzymes, leading to breaks in single-stranded DNA. This transient, reversible damage activates protein kinases ATR and CHK1, which then phosphorylate and activate p53, the authors say. — B.T.
pH2AX-positive cells (green) accumulate at DNA damage sites.
“DNA synthesis from unbalanced nucleotide pools causes limited DNA damage that triggers ATR-CHK1-dependent p53 activation” by Kedar Hastak, Rajib K. Paul, Mukesh K. Agarwal, Vijay S. Thakur, A. R. M. Ruhul Amin, Sudesh Agrawal, R. Michael Sramkoski, James W. Jacobberger, Mark W. Jackson, George R. Stark, and Munna L. Agarwal (see pages 6314–6319)
DEVELOPMENTAL BIOLOGY
Adult stem cells found in pituitary
The anterior pituitary gland is essential for regulating the balance of endocrine hormones in adult animals. Although the gland is fully formed in newborns, it undergoes dramatic remodeling during the animal's life, with a rapid growth spurt after birth, as the gland changes in response to various hormones. This growth pattern is consistent with the presence of multipotent stem cells, but no such cells have previously been found. Anatoli Gleiberman et al. identified a group of nestin-expressing adult stem cells in the perilumenal region of the pituitary and tracked their development through embryonic stages and in the adult organism. These stem cells are able to generate the six endocrine cell types seen in the pituitary but do not play a significant role during the embryonic development of the gland. The adult pituitary gland differs from other organs in that it contains a mosaic of cells derived from adult stem cells and embryonic lineages, which may enable the gland to quickly respond to physiological changes, say the authors. — B.T.
Nestin-positive adult stem cells during early pituitary development in vitro.
“Genetic approaches identify adult pituitary stem cells” by Anatoli S. Gleiberman, Tatyana Michurina, Juan M. Encinas, Jose L. Roig, Peter Krasnov, Francesca Balordi, Gord Fishell, Michael G. Rosenfeld, and Grigori Enikolopov (see pages 6332–6337)
MEDICAL SCIENCES
A crystal ball for breast cancer diagnosis
Better diagnoses lead to better treatment, but for breast cancers it is often difficult to distinguish deadly metastatic tumors from the estimated 80% of more easily treated nonmetastatic tumors. A protein that halts the spread of mammary tumors in mice may be the key to predicting metastatic potential for breast cancer patients. Nigel Crawford et al. inserted the gene for the mammalian bromodomain protein Brd4 into a line of metastatic mouse mammary tumor cells and found that the invasiveness of the tumor cells in vitro was significantly stunted. Implanting Brd4-containing tumor cells into a mouse suppressed the ability to form large tumors. The expression of Brd4 changed the expression of many genes, which together formed a unique signature. A human Brd4 gene signature mapped from the mouse genes was used to probe microarray expression data from five groups of breast cancer patients. In all groups, patients with a Brd4-positive signature survived longer and developed fewer metastatic tumors, indicating that Brd4 expression signatures accurately predict the severity of breast cancer. Similar microarray-based diagnoses suffer from a “black-box” stigma, but the clear molecular role of Brd4 in metastasis conveys a more fundamental meaning to the results, the authors say. — C.E.
“Bromodomain 4 activation predicts breast cancer survival” by Nigel P. S. Crawford, Jude Alsarraj, Luanne Lukes, Renard C. Walker, Jennifer Officewala, Howard H. Yang, Maxwell P. Lee, Keiko Ozato, and Kent W. Hunter (see pages 6380–6385)
NEUROSCIENCE
Tracking power consumption in the brain
The brain consumes power in the form of ATP as it maintains the ionic gradients necessary for action potentials and neuronal signaling. However, the total concentration of ATP remains constant over a wide range of conditions. According to previous research, the flux of ATP produced oxidatively by the F1F0-ATPase provides the best measure of power consumption. Fei Du et al. report that in vivo 31P magnetic resonance spectroscopy (MRS), combined with a saturation transfer method, can track power consumption in the brain under varied neuronal activity. The authors obtained brain 31P spectra from rats treated with one of three chemical agents that reduce brain activity: isoflurane, α-chloralose, and pentobarbital. At high doses of pentobarbital, EEG traces flatline in an “isoelectric” state, in which all spontaneous brain electrical activity is shut down. The authors found that the measured ATPase flux is tightly correlated to the EEG level and is reduced by 50% in the isoelectric state, suggesting that significant power is required for “housekeeping” operations. Du et al. say that in vivo 31P MRS may provide a useful, noninvasive tool for tracking brain power consumption and for studying the critical roles of ATP in brain function and disease. — K.M.
“Tightly coupled brain activity and cerebral ATP metabolic rate” by Fei Du, Xiao-Hong Zhu, Yi Zhang, Michael Friedman, Nanyin Zhang, Kâmil Uğurbil, and Wei Chen (see pages 6409–6414)
NEUROSCIENCE
Inner workings of a modulator
Neurotransmitter output is modulated at many synapses via G protein-coupled receptors (GPCRs). Eugene Silinsky demonstrates how the adenosine GPCR inhibits calcium influx, and hence excitatory postsynaptic potentials, at neuromuscular junctions in mice. He reports that a complex of SNAREs—the vesicle-bound synaptobrevin and the plasma membrane proteins SNAP-25 and syntaxin—stand ready to fuse the vesicle with the membrane and release the neurotransmitter when calcium flows in through an associated channel. Because adenosine, which inhibits this process, has a more potent effect in Rab3A−/− mutants, the author investigated the consequences of cleaving SNARE proteins with botulinum toxins A, C, D, and E, each of which has a specific molecular target. Silinsky proposes a model in which the Gβγ moiety released by adenosine can interact with several different sites in the complex to inhibit the calcium channel. In both wild-type and Rab3A−/− mice, cleavage of both membrane-associated SNAREs at central locations abolished the effect of adenosine. Cleavage of synaptobrevin enhanced adenosine potency, but only in Rab3A−/− mice. The author suggests that RIM, a molecule that normally docks Rab3A to the membrane and assists in SNARE priming, may alter SNARE–channel conformation, and hence Gβγ binding site availability, in the mutants. — K.M.
“Selective disruption of the mammalian secretory apparatus enhances or eliminates calcium current modulation in nerve endings” by Eugene M. Silinsky (see pages 6427–6432)
