Faculty Bibliography

Cancer cells are able to proliferate at accelerated rates within the confines of a three-dimensional (3D) extracellular matrix (ECM) that is rich in type I collagen. The mechanisms used by tumor cells to circumvent endogenous antigrowth signals have yet to be clearly defined. We find that the matrix metalloproteinase, MT1-MMP, confers tumor cells with a distinct 3D growth advantage in vitro and in vivo. The replicative advantage conferred by MT1-MMP requires pericellular proteolysis of the ECM, as proliferation is fully suppressed when tumor cells are suspended in 3D gels of protease-resistant collagen. In the absence of proteolysis, tumor cells embedded in physiologically relevant ECM matrices are trapped in a compact, spherical configuration and unable to undergo changes in cell shape or cytoskeletal reorganization required for 3D growth. These observations identify MT1-MMP as a tumor-derived growth factor that regulates proliferation by controlling cell geometry within the confines of the 3D ECM

During the ribosomal translocation, the binding of elongation factor G (EF-G) to the pretranslocational ribosome leads to a ratchet-like rotation of the 30S subunit relative to the 50S subunit in the direction of the mRNA movement. By means of cryo-electron microscopy we observe that this rotation is accompanied by a 20 A movement of the L1 stalk of the 50S subunit, implying that this region is involved in the translocation of deacylated tRNAs from the P to the E site. These ribosomal motions can occur only when the P-site tRNA is deacylated. Prior to peptidyl-transfer to the A-site tRNA or peptide removal, the presence of the charged P-site tRNA locks the ribosome and prohibits both of these motions

Trafficking of trophic factors in axons can occur in a retrograde and anterograde direction. Recent findings bring further support for a vesicle-based process for retrograde transport but raise new questions that need to be pursued. Unraveling the exact mechanisms that account for retrograde transport of neurotrophins and their receptors will reveal the cellular requirements for propagating trophic signals over long distances

Stress triggered cardiovascular disorders are associated with elevated activity of the sympathetic nervous system, the major source of elevated plasma norepinephrine levels. Our previous studies revealed that administration of adrenocorticotropic hormone (ACTH) increases the gene expression of norepinephrine biosynthetic enzymes and several neuropeptides in rat sympathetic ganglia as much as stress. Here, we examine whether an ACTH-responsive receptor is expressed in rat superior cervical (SCG) and stellate ganglia (StG). Using reverse transcriptase-polymerase chain reaction (RT-PCR) we found expression of MC-2 receptor mRNA in these ganglia. Identical DNA fragments were amplified with mRNA from SCG, StG or from adrenal cortex. Sequencing revealed extensive homology to published sequences of mouse and human MC-2 receptor. Real time PCR was used to quantitate MC-2 receptor mRNA levels in the SCG under basal conditions and following immobilization stress. Immobilization stress triggered a large increase in MC-2 receptor mRNA in SCG. The results provide the first evidence that rat sympathetic ganglia express MC-2 receptor gene and are a target tissue for the peripheral actions of ACTH in response to stress.

Circulating neutrophils play a key role both in the systemic inflammatory response and in complications of bacterial infection such as septic shock and septic multiple organ dysfunction syndrome. We have analyzed gene expression patterns in human neutrophils stimulated by E. coli lipopolysaccharide (LPS), with or without prior exposure to LPS, using differential display and oligonucleotide chip techniques. We identified 307 genes that were activated or repressed after treatment with LPS at 10 ng/ml and 385 genes after LPS at 100 ng/ml, compared with untreated neutrophils. The two sets included many transcription factors, cytokines, chemokines, interleukins, and surface antigens, as well as members of the toll-like receptor, Rel/NF-kappaB, and immune mediator gene families. Time course analysis showed that the early and late neutrophil responses to LPS share some common mechanisms, but many changes in gene expression are transient or late to develop. Neutrophils also showed a priming response to LPS, in which 97 genes significantly changed expression on re-exposure to lower dose LPS and were analyzed by unsupervised hierarchical clustering. These findings indicate that the neutrophil is a transcriptionally active cell responsive to environmental stimuli and capable of a complex series of both early and late changes in gene expression. Supplementary material for this article can be found on the Journal of Cellular Biochemistry website (http://jws-edci.interscience.wiley.com:8998/jpages/0730-2312/suppmat/89/v 89.page.html)

Evolutionary biologists have long commented on a seemingly universal "rule" of nature-that in large taxonomic assemblages from groups as diverse as bacteria, plants, insects, marine invertebrates, fish, reptiles, amphibians, birds, and mammals, there exists a frequency distribution of body sizes among species that is highly skewed to the right (positive skewness). This distribution reflects the strong inverse, or negative, relationship often noted between mean body size of taxa and the number of species they contain--i.e., the observation that small body size is often associated with high species diversity (speciosity). This is sometimes "explained" by recourse to the idea that smaller-bodied taxa are able to subdivide their environments more finely than larger-bodied taxa. With but few exceptions, the applicability of this "rule" to the Order Primates has not been studied in any detail. In this study I address the following questions of (paleo)anthropological interest: (1) How speciose is the Order Primates? (2) Does this biological "rule" characterize the Order Primates (at any taxonomic level) in any meaningful way? (3) Does the association between speciosity and body mass within the Order Primates provide any useful models for interpreting and/or predicting speciosity in the fossil primate record? Using phylogenetically independent contrasts methods, I conclude that the answers to those three questions are: (1) not very; (2) no; and (3) not particularly (with the possible exception of larger-bodied taxa).

Although estrogen is best known for its effects on the maturation and differentiation of the primary and secondary sex organs, increasing evidence suggests that its influence extends beyond this system, and its activity in the CNS may initiate, or influence our susceptibility to neurodegenerative decline. Estrogen has been proposed to act as a neuroprotectant at several levels, and it is probable that deprivation of estrogen as a result of menopause exposes the aging or diseased brain to several insults. In addition, estrogen deprivation is likely to initiate or enhance degenerative changes caused by oxidative stress, and to reduce the brain's ability to maintain synaptic connectivity and cholinergic integrity leading to the cognitive decline seen in aged and disease-afflicted individuals