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Directed cell migrations are important for development, but the signaling pathways and mechanisms responsible for guiding cell migration in vivo are poorly understood. Migration of border cells during Drosophila oogenesis is a simple and attractive model system in which to address these questions. We demonstrate that PVR, a receptor tyrosine kinase related to mammalian PDGF and VEGF receptors, acts...
HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. Recent studies have defined posttranslational modification by prolyl hydroxylation as a key regulatory event that targets HIF-α subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylation complex. Here, we define a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans, and use a genetic...
Studies on several recently discovered error-prone DNA polymerases reveal novel structures that may explain the low fidelity of this general class of enzymes, a number of which are involved in the replicative bypass (translesion synthesis) of base damage in DNA.
Loss of telomere function can induce cell cycle arrest and apoptosis. To investigate the processes that trigger cellular responses to telomere dysfunction, we crossed mTR-/- G6 mice that have short telomeres with mice heterozygous for telomerase (mTR+/-) that have long telomeres. The phenotype of the telomerase null offspring was similar to that of the late generation parent, although only half of...
Expression of the yeast transcription factor Hac1p, which controls the unfolded protein response, is regulated posttranscriptionally. Hac1p is only produced when an intron at the 3' end of its mRNA is removed by a nonconventional, regulated splicing reaction. We show that a previously unrecognized base-pairing interaction between the intron and the 5' untranslated region is required and sufficient...
The mechanism by which peptide release factor RF3 recycles RF1 and RF2 has been clarified and incorporated in a complete scheme for translation termination. Free RF3 is in vivo stably bound to GDP, and ribosomes in complex with RF1 or RF2 act as guanine nucleotide exchange factors (GEF). Hydrolysis of peptidyl-tRNA by RF1 or RF2 allows GTP binding to RF3 on the ribosome. This induces an RF3 conformation...
Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) is a DinB homolog that belongs to the recently described Y-family of DNA polymerases, which are best characterized by their low-fidelity synthesis on undamaged DNA templates and propensity to traverse normally replication-blocking lesions. Crystal structures of Dpo4 in ternary complexes with DNA and an incoming nucleotide, either correct or incorrect,...
Availability of the mouse genome sequence will have a major impact on the study of vertebrate evolution, mammalian biology, and animal models of human disease. Resources to explore genome biology in mice will maximize the effect of this watershed event.
Like other enveloped viruses, HIV-1 uses cellular machinery to bud from infected cells. We now show that Tsg101 protein, which functions in vacuolar protein sorting (Vps), is required for HIV-1 budding. The UEV domain of Tsg101 binds to an essential tetrapeptide (PTAP) motif within the p6 domain of the structural Gag protein and also to ubiquitin. Depletion of cellular Tsg101 by small interfering...
The stalling of DNA replication forks that occurs as a consequence of encountering DNA damage is a critical problem for cells. RecG protein is involved in the processing of stalled replication forks, and acts by reversing the fork past the damage to create a four-way junction that allows template switching and lesion bypass. We have determined the crystal structure of RecG bound to a DNA substrate...
The C. elegans genes ced-2, ced-5, and ced-10, and their mammalian homologs crkII, dock180, and rac1, mediate cytoskeletal rearrangements during phagocytosis of apoptotic cells and cell motility. Here, we describe an additional member of this signaling pathway, ced-12, and its mammalian homologs, elmo1 and elmo2. In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations...
Hypoxia-inducible factor 1 (HIF-1) is a global regulator of cellular and systemic O 2 homeostasis in animals. A molecular basis for O 2 -regulated expression of the HIF-1α subunit has now been determined, providing a mechanism for changes in gene expression in response to changes in cellular oxygenation.
SUMO is covalently linked to a variety of cellular proteins. Three groups now describe related E3-like factors that enhance transfer of SUMO to specific proteins. This family of factors includes proteins important for chromosome condensation, signal transduction, and ion channel biogenesis.
The polytopic membrane protein Rhomboid-1 promotes the cleavage of the membrane-anchored TGFα-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Until now, the mechanism of this key signaling regulator has been obscure, but our analysis suggests that Rhomboid-1 is a novel intramembrane serine protease that directly cleaves Spitz. In accordance with the putative Rhomboid...
The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2α physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2α, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2α represses p53-dependent...
Asymmetric cell division depends on the polarization of the dividing cell for the correct alignment of the mitotic spindle and the localization of cytoplasmic determinants. Receptor-independent activation of heterotrimeric G proteins by the Drosophila GoLoco protein Partner of Inscuteable seems to represent a novel mechanism to control these events.
DNA damage-induced acetylation of p53 protein leads to its activation and either growth arrest or apoptosis. We show here that the protein product of the gene hSIR2 SIRT1 , the human homolog of the S. cerevisiae Sir2 protein known to be involved in cell aging and in the response to DNA damage, binds and deacetylates the p53 protein with a specificity for its C-terminal...
The C/EBPα transcription factor is required for differentiation of adipocytes and neutrophil granulocytes, and controls cellular proliferation in vivo. To address the molecular mechanisms of C/EBPα action, we have identified C/EBPα mutants defective in repression of E2F-dependent transcription and found them to be impaired in their ability to suppress cellular proliferation, and to induce adipocyte...
The conversion of a ribosomal RNA transcript to a cytoplasmic ribosome requires hundreds of accessory RNA and protein factors. Two papers published recently in Molecular Cell provide first looks at the association of these processing factors with the intermediates in ribosome synthesis (Harnpicharnchai et al., 2001; Bassler et al., 2001).
A growing body of evidence indicates that plant transcription factors move between cells. A recent paper by Nakajima et al. (2001) shows that movement of the SHORTROOT protein provides a mechanism for signaling positional information between cell layers of the root.
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