f box proteins

..This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer...

..SCF complexes couple protein kinase signaling pathways to the control of protein abundance...

..Collectively, our results reveal a molecular mechanism that may account for how ubiquitin controls a broad spectrum of cellular activities...

..Different skp1 mutants arrest cells in either G1 or G2, suggesting a connection between regulation of proteolysis in different stages of the cycle...

..We conclude that PiSLF encodes the pollen self-incompatibility determinant...

..By filling in a hydrophobic cavity at the protein interface, auxin enhances the TIR1-substrate interactions by acting as a 'molecular glue'. Our results establish the first structural model of a plant hormone receptor...

..Here we explore a unifying and structurally detailed view of SCF-mediated proteolytic control of cellular processes that has been revealed by recent studies...

..We suggest that interactions between c-Myc and Fbw7gamma within the nucleolus regulate c-Myc's growth-promoting function and that c-Myc activation is likely to be an important oncogenic consequence of Fbw7 loss in cancers...

..Here we show that three additional F box proteins, called AFB1, 2, and 3, also regulate auxin response...

..Our data extend previous observations that link Myc function to the cellular response to DNA damage...

..Here we show that this modification involves the direct binding of auxin to TIR1 and thus that TIR1 is an auxin receptor mediating transcriptional responses to auxin...

..Interestingly, viruses and even pathogenic bacteria have also found ways to hijack the plant SCF and to reprogram it for their own purposes...

..Thus, Mos and Erp1 collaboratively establish and maintain metaphase II arrest in Xenopus eggs. The link between Mos and Erp1 provides a molecular explanation for the integral mechanism of CSF arrest in unfertilized vertebrate eggs...

..These results provide novel insight into the regulation of Slug, a protein that plays a central role in neural crest precursor formation, as well as in developmental and pathological epithelial to mesenchymal transitions...

..Multiple F-box proteins contribute to cyclin E stability in yeast, suggesting an overlap in SCF E3 ligase specificity that allows combinatorial control of cyclin E degradation...

..Thus, Fbxl3(Ovtm) defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period...

..Accumulation of c-Myc was also apparent in mouse Fbw7-/- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively...

..Taken together, these data illuminate the molecular basis for the G1/S transition in budding yeast and suggest a general mechanism for phosphorylation-targeted ubiquitination in eukaryotes...

..Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL...

..Together, our results suggest that Dia2 protein turnover does not involve an autocatalytic mechanism and that Dia2 proteolysis is inhibited by activation of the replication stress response...

..Cdk1 and Aurora kinase studies have been facilitated by small-molecule inhibitors, but few if any potent Plk1 inhibitors have been identified...

..Our findings suggest that the amino-terminal domains of other F box proteins might also play an analogous regulatory role, controlling the localization of the cognate SCF complexes.

..In consequence, the c-Myb protein was markedly stabilized by the substitution of Thr-572 to Ala. These observations suggest that SCF(Fbw7) ubiquitin ligase regulates phosphorylation-dependent degradation of c-Myb protein...

..Our data suggest that LT competes with cellular proteins for Fbw7 binding in a substrate-like fashion...

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..We propose that Gal4 ubiquitylation and destruction are required for initiation-competent transcription complexes to transition to fully mature elongating complexes capable of appropriate mRNA processing...

..Furthermore, in terms of recognition specificity, diploid pollen grains carrying PpsS-3'-haplotype are equal to monoploid pollen grains carrying the other functional S-haplotype...

..Post-translational control of SCF(Met30) assembly by a physiological stress to allow rapid induction of a protective gene expression program represents a novel mode of regulation in the ubiquitin system...

..Tec1T273V blocks Tec1 ubiquitination and degradation and allows the induction of filamentation genes in response to pheromone. Thus, Fus3 inhibits filamentous growth during mating by degrading Tec1...

..Transfection with an small interfering RNA duplex directed against Plk1 caused the accumulation of Emi1 in mitotically arrested HeLa cells. It is suggested that phosphorylation of Emi1 by Plk1 is involved in its degradation in mitosis...

..Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins...

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..We propose that p53-dependent loss of Fbxw7 leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers...

..These data suggest essential functions for Fbw7 in controlling cyclin E and Notch signaling pathways in the mouse...

..Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis...

..These data support the hypothesis that Plk1 activates the APC by directing the SCF-dependent destruction of Emi1 in prophase...

..This neuron-specific, SCF-like complex therefore provides a localized signal to attenuate presynaptic differentiation...

..These results identify Emi2 as a candidate CSF maintenance protein...

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..These studies show in intact oocytes that the interaction of Emi2 with Cdc20 links activating stimuli to meiotic resumption at fertilization and during parthenogenesis in mammals...

..This represents a potentially important mechanism by which pRb and p53 dysfunction may contribute to tumorigenesis through the generation of genomic instability...

..Importantly, we identity a novel, specific role for Mcl1 in the transcriptional silencing and the localisation of CENP-A at the centromeres...

..Finally, the different topologies of the phylogenetic trees produced using available SLF-related sequences and those produced using S-RNase sequences suggests that pollen S and the S-RNase have different evolutionary histories...

..Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer...

..The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping...

..These results clarify the direct link of the classical Mos-MAPK pathway to Erp1 in meiotic arrest of vertebrate oocytes...

..Furthermore, analysis of different fbh1 mutant alleles suggests that both the F-box and helicase activities of Fbh1 contribute to controlling Rhp51...

..Focus formation of Fbh1 protein was induced by treatment that damages DNA. Thus, the F-box DNA helicase appears to process toxic recombination intermediates, the formation of which is dependent on the function of Rhp51...

..SCF(Grr1)-mediated degradation of Hof1 may thus represent a novel mechanism to couple exit from mitosis with initiation of cytokinesis...

..We propose that the balance of Evi5 and Polo-like kinase activities determines the timely accumulation of Emi1 and cyclin, ensuring mitotic fidelity...

..Clinical evidence also suggests that dysregulation of these F-box proteins contributes to human cancers...

..Finally, TIR1 synthesized in insect cells binds Aux/IAA proteins in an auxin-dependent manner. Together, these results indicate that TIR1 is an auxin receptor that mediates Aux/IAA degradation and auxin-regulated transcription...

..Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis...

..These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc...

..However, connections between the Plx1 pathway and the CaMKII pathway have not been identified...

..In this review we discuss the activities of the SCF(Fbw7) in the context of its role as a tumor suppressor and highlight recent findings demonstrating that dominant oncogenes disable Fbw7 function...

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..This numerical wizardry suggests how analog inputs can be rectified to digital outputs. Unraveling the counting mechanism promises to generate new insights into the architecture of protein nanoprocessors...

..These findings implicate archipelago in developmentally regulated degradation of Cyclin E and potentially in the pathogenesis of human cancers...

..The gene encoding hCdc4 was found to be mutated in a cell line derived from breast cancer that expressed extremely high levels of cyclin E...

..Importantly, Skp1p was the only major partner that copurified with Rcy1p. Our results thus suggest that a complex composed of Rcy1p and Skp1p but not other SCF components may play a direct role in recycling of internalized proteins...

..We propose that coupled activation and destruction link the assembly of Cbf3p to the duplication of centromeres in S phase...

..We propose that SEL-10 promotes the ubiquitin-mediated turnover of LIN-12/Notch proteins, and discuss potential roles for the regulation of lin-12/Notch activity by sel-10 in cell fate decisions and tumorigenesis...

..Thus, understanding the mechanisms that confer specificity to the ubiquitin system will allow the development of novel therapeutic approaches to target aberrations in this pathway underlying tumorigenesis and other human pathologies...

..The complementary C-terminal segment of SIC1 binds to the S-phase cyclin CLB5, indicating a modular structure for SIC1...

..As many F-box proteins can be found in sequence databases, it appears that a host of cellular pathways will be regulated by SCF-dependent proteolysis...

..By the two-hybrid method, we showed that Met30p interacts with Met4p and identified a region of Met4p involved in this interaction. Further analysis reveals that expression of Met30p is essential for cell viability...

..These data suggest that E2F can activate both transcription of cyclin A and the hEmi1-dependent stabilization of APC(Cdh1) targets, such as cyclin A, to promote S phase entry...

..Ubiquitination of phosphorylated I kappa B alpha can be catalyzed by the ROC1 immunocomplex in vitro. Hence, combinations of ROC/APC11 and cullin proteins proteins potentially constitute a wide variety of ubiquitin ligases...

..Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein-protein interactions...

..We propose that casein kinase I plays a similar role in both nutritional signaling pathways by phosphorylating pathway components and targeting them for ubiquitination by SCFGrr1...

..We find that Emi1 binds the substrate-binding region of Cdc20 and prevents substrate binding to the APC, illustrating a novel mechanism of APC inhibition...

..When bound to Cdc28-43244, Cln2HA was recognized and polyubiquitinated by SCF-Grr1. The Cdc28-43244 mutant thus reveals an unexpected complexity in the degradation of polyubiquitinated Cln2HA by the proteasome...

..We conclude that Cdc53/Hrt1 comprise a highly conserved module that serves as the functional core of a broad variety of heteromeric ubiquitin ligases...

..Signal-induced destruction of a transcription factor for a competing pathway provides a mechanism for signaling specificity...

..Our results suggest that the plant counterpart of yeast Skp1 is probably also instrumental in ubiquitin-mediated proteolysis of specific proteins via an SCF-like pathway...

..Our study provides an example of an F-box protein acting as an adaptor protein that can mediate the neddylation of a non-cullin substrate...

..Once established, however, F-actin is not required for the maintenance of Cdc4p and Myo2p medial rings, suggesting that the attachment of Cdc4p and Myo2p to the division site involves proteins other than actin itself...

..The Ca2+-activated pathway may play a role in the rapid inactivation of Hsl1 at the cell cycle stage(s) when APC activity is low...

..Based on our experience in reconstituting Sic1 ubiquitination, we suggest some parameters to consider that should be generally applicable to the study of different SCF complexes and other ubiquitin ligases...

..Genetic analyses demonstrated a complex effect of cadmium on cell cycle regulation that might be important to safeguard cellular and genetic integrity when cells are exposed to heavy metals...

..Cic1 interacts in vitro and in vivo with Cdc4, suggesting a function as a new kind of substrate recruiting factor or adaptor associated with the proteasome...

..However, stabilization through mutation of three N-terminal phosphorylation sites or of the single C-terminal phosphorylation site leads to dominant lethality when combined with certain mutations in the anaphase-promoting complex...

..Our data reveal a novel proteolysis-independent function for Cdc34/SCF and indicate that ubiquitination of transcription factors can be utilized to directly regulate their activities...

..Taken together, these findings suggest that the SCF(Cdc4) ubiquitin ligase complex regulates Clb6 turnover and that the functional differences exhibited by Clb5 and Clb6 arise from the distinct mechanisms controlling their stability...

..We propose that the BTB/POZ domain defines a recognition motif for the assembly of substrate-specific RING/cullin 3/BTB ubiquitin ligase complexes...

..This suggests that all Cdc34p substrates are ubiquitinated by a similar high molecular weight complex...

..We discuss implications of this finding for function of other ubiquitin ligases...

..In contrast, the Cdc34-Cdc53-Skp1 E2/E3 core complex is required for all three functions. Combinatorial control of SCF complexes may provide a basis for the regulation of diverse cellular processes...

..These findings indicate that the SCF(Cdc4) complex regulates S phase entry not only through degradation of Sic1, but also through degradation of Swi5...

..Our results show that Far1p is regulated by ubiquitin-mediated proteolysis and suggest that phosphorylation of Far1p by the Cdc28p-Clnp kinase is part of the recognition signal for ubiquitination...

..These features account for the observed phosphorylation threshold in Sic1 recognition and suggest an equilibrium binding mode between a single receptor site in Cdc4 and multiple low-affinity CPD sites in Sic1...

..This structure provides insights into the binding interaction and how a precise mechanism involving multiple regulatory phosphorylations may be mediated by a single binding site...

..Constitutive overexpression of either wild-type or stable Cdc6p does not induce re-replication and does not induce assembly of pre-replicative complexes after DNA replication is complete...

..Co-transfection of sel-10 and APP cDNAs in HEK293 cells leads to an alteration in the metabolism of APP and to an increase in the production of amyloid beta-peptide, the principal component of amyloid plaque in Alzheimer's disease...

..Furthermore, Grr1 bound Skp1 directly in vitro. These results strongly suggest that Grr1 functions in the ubiquitin pathway through association with Skp1...

..These results suggest that attenuation of SCF(Cdc4)-dependent proteasomal degradation of PGC-1alpha has a role in mediating the PGC-1alpha-dependent transcriptional response to oxidative stress...

..Understanding how SBP5 blocks mitosis and induces apoptosis may provide important insight for creating new cancer chemotherapeutic drugs that act similarly or synergistically with vinca alkaloids and Taxol. ..

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..As the mechanisms of the ubiquitin-mediated proteolysis of cell cycle regulators are unraveled, this team is committed to the integration of its basic research results with an understanding of malignant transformation. ..

..It is anticipated that the results of our studies will have an impact on both basic science and cancer biology. ..

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..Under Aim 3, the principal investigator will also clone and characterize three proteins that he has found associated specifically with Fb13 in vivo. ..

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..Targeting SAG in cancer cells, via siRNA silencing or small molecule inhibitors, would, therefore, be a valid antianglogenesis therapy. ..

..Defects in the pathway contribute to many disease processes including cancers. This study will advance our understanding of the ubiquitin/proteasome pathway in cell function. ..

..These initial studies will set the stage for a more detailed investigation of the mechanism of SAG mediated suppression of apoptosis. ..

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..Furthermore, we will provide a molecular basis for future screening of drugs that may act as chemo-prevention agents via SAG induction. ..

..Furthermore, we will provide a molecular basis for future screening of drugs that may act as chemo-prevention agents via SAG induction. ..

..Furthermore, we will provide a molecular basis for future screening of drugs that may act as chemo-prevention agents via SAG induction. ..

..This could be particularly rewarding in the case of Slimb and its mammalian homolog beta-TrCP, which recognize a variety of phosphotargets and have important roles in development, apoptosis, inflammatory responses and cancer. ..

..Execution of studies outlined in this application will provide a major advance in the conceptual framework for how sepsis causes lung impairment by altering surfactant production. ..

..As such, it is a crucial step towards developing treatment strategies for tumors associated with this pathway. ..

..Therefore, the information gained from the proposed studies will be of direct relevance to cancer biology and other proliferative diseases. ..

..In the future, this knowledge may support the design of compounds that specifically interfere with aspects of SCF functions involved in tumor development and progression. ..

..By this multidisciplinary approach, these studies will provide novel insights into biological processes relevant for Vif function during HIV replication and will also facilitate antiviral drug discovery for HIV/AIDS. ..

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..This will be achieved using specific membrane permeable peptides designed on the basis of our structural and biochemical information. ..

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..Understanding these regulatory mechanisms is central to understanding a range of human conditions including cancer, developmental defects and heritable disease. ..