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‣ From oligonucleotide shapes to genomic SELEX: Novel biological regulatory loops

Gold, Larry; Brown, David; He, Yi-yuan; Shtatland, Timur; Singer, Britta S.; Wu, Yan
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 07/01/1997 Português
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The SELEX method and oligonucleotide combinatorial chemistry discovery process yields high-affinity/high-specificity ligands for virtually any molecular target. Typically, the enormous starting libraries used in the SELEX process contain 1014–1015 sequences. We now ask if the smaller sequences, complexity of extant organisms, and evolutionary history provide useful interactions between oligonucleotides and at least some unexpected targets. That is, do organisms contain a robust “linkage map” between their oligonucleotides and proteins and/or small molecules that enriches life?

‣ Expression of p24, a novel p21Waf1/Cip1/Sdi1-related protein, correlates with measurement of the finite proliferative potential of rodent embryo fibroblasts

Mazars, G. Raoul; Jat, Parmjit S.
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 07/01/1997 Português
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447.82504%
Normal mammalian fibroblasts undergo a limited number of divisions when cultured in vitro before entering a state of replicative senescence. The molecular basis for the determination of the finite mitotic potential is not known. Nevertheless, simian virus 40 T antigen, among other oncogenes, is able to prevent senescence in rodent embryo fibroblasts. T antigen immortalized cells are dependent upon this protein for maintaining growth once their normal mitotic life span has elapsed. Even though the mechanism that measures the finite mitotic potential of rodent fibroblasts is not known, it has been shown that it continues to function normally in the presence of this immortalizing gene. Accumulation of cyclin-dependent kinase inhibitors such as p21Waf1/Cip1/Sdi1 could potentially be a component of the mechanism that determines the finite life span. Here we show that accumulation of p21Waf1/Cip1/Sdi1 does not correlate with this biological counting mechanism, but we have identified p24, a p21Waf1/Cip1/Sdi1-related protein, whose accumulation does correlate with the measurement of the finite proliferative potential of rodent embryo fibroblasts and suggest that sequestration might be a mechanism by which its activity is regulated.

‣ Newborn primate infants are entrained by low intensity lighting

Rivkees, Scott A.; Hofman, Paul L.; Fortman, Jeffrey
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 07/01/1997 Português
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447.82504%
At the present time we do not know when the circadian timing system of human infants becomes responsive to light. Because of human study limitations, it is not currently possible to address this issue in clinical studies. Therefore, to provide insights into when the circadian system of humans becomes responsive to light, baboons were studied. We first assessed if the biological clock located in suprachiasmatic nuclei (SCN) is responsive to light at birth. When term newborn infants were exposed to bright light at night (5000 lux), SCN metabolic activity and c-fos mRNA expression increased, indicating the presence of photic responsiveness. When photic entrainment of developing rhythmicity was examined in infants, low intensity (200 lux) cycled lighting was sufficient to entrain circadian phase. However, low intensity lighting was not sufficient to induce changes in SCN metabolic activity or c-fos mRNA expression. Phase–response studies indicated that light exposure (200 lux) before the onset of activity most effectively shifted circadian phase. These data provide direct evidence that the SCN are responsive to visually mediated light information in a primate at birth. Further consideration of lighting conditions that infants are exposed to is therefore warranted.

‣ Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: Implications for the mechanism of StAR action

Arakane, Futoshi; Sugawara, Teruo; Nishino, Hideaki; Liu, Zhiming; Holt, John A.; Pain, Debkumar; Stocco, Douglas M.; Miller, Walter L.; Strauss, Jerome F.
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 26/11/1996 Português
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447.82504%
Steroidogenic acute regulatory protein (StAR) plays a critical role in steroid hormone biosynthesis, presumably by facilitating the delivery of cholesterol to P450scc in the inner mitochondrial membranes. StAR is synthesized as a 37-kDa preprotein that is processed to a 30-kDa mature form by cleavage of an N-terminal mitochondrial import sequence. To identify structural features required for StAR biological activity, we mutated the human StAR cDNA, including the deletion of N- and C-terminal sequences, and examined the ability of the mutants to promote steroidogenesis and enter the mitochondria of transfected COS-1 cells. Deletion of up to 62 residues from the N terminus (N-62) did not significantly affect steroidogenesis-enhancing activity. The N-terminal deletion mutants were associated with mitochondria-enriched fractions, but import and processing were progressively impaired with increasing length of the deletion. Immunogold electron microscopy and in vitro import assays showed that the active N-62 mutant was not imported into the mitochondria. Removal of the 28 C-terminal amino acids (C-28) inactivated StAR. Deletion of the C-terminal 10 amino acids (C-10) reduced steroidogenic activity by 53%, while truncation of the last 4 amino acids had no effect. The C-28 mutant StAR was not efficiently imported into mitochondria or processed...

‣ Dimerization of Ste5, a mitogen-activated protein kinase cascade scaffold protein, is required for signal transduction

Yablonski, Deborah; Marbach, Irit; Levitzki, Alexander
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 26/11/1996 Português
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447.82504%
The mitogen-activated protein kinase cascade of the Saccharomyces cerevisiae pheromone response pathway is organized on the Ste5 protein, which binds each of the kinases of the cascade prior to signaling. In this study, a structure–function analysis of Ste5 deletion mutants uncovered new functional domains of the Ste5 protein and revealed that Ste5 dimerizes during the course of normal signal transduction. Dimerization, mediated by two regions in the N-terminal half of Ste5, was first suggested by intragenic complementation between pairs of nonfunctional Ste5 mutants and was confirmed by using the two-hybrid system. Coimmunoprecipitation of differently tagged forms of Ste5 from cells in which the pathway has been activated by Ste5 overexpression further confirmed dimerization. A precise correlation between the biological activity of various Ste5 fragments and dimerization suggests that dimerization is essential for Ste5 function.

‣ Visualization of supercoiled DNA with atomic force microscopy in situ

Lyubchenko, Yuri L.; Shlyakhtenko, Luda S.
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 21/01/1997 Português
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447.82504%
Tertiary structure of supercoiled DNA is a significant factor in a number of genetic functions and is apparently affected by environmental conditions. We applied atomic force microscopy (AFM) for imaging the supercoiled DNA deposited at different ionic conditions. We have employed a technique for the sample preparation that permits high-resolution AFM imaging of DNA bound to the surface in buffer solutions without drying the sample (AFM in situ). The AFM data show that at low ionic strength, DNA molecules are loosely interwound supercoils with an irregular shape. Plectonemic superhelices are formed in high-concentration, near-physiological salt solutions. At such ionic conditions, superhelical loops are typically separated by regions of close helix–helix contacts. The data obtained show directly and unambiguously that overall geometry of supercoiled DNA depends dramatically on ionic conditions. This fact and the formation of close contacts between DNA helices are important features of supercoiled DNA related to its biological functions.