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CDK8/19 Mediator kinases potentiate induction of transcription by NFκB (2017)

Chen, Mengqian ; Liang, Jiaxin ; Ji, Hao ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2017; 114(38): 10208-10213. Published 2017 Aug 30. doi: 10.1073/pnas.1710467114.

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Publication Date: 2017-08-30

Description: The nuclear factor-κB (NFκB) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NFκB show significant side effects, possibly due to sustained NFκB suppression. Drugs affecting induced, but not basal, NFκB activity may have the potential to provide therapeutic benefit without associated toxicity. NFκB activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NFκB-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNFα. On NFκB activation, CDK8/19 are corecruited with NFκB to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene-specific manner. Genes coregulated by CDK8/19 and NFκB includeIL8,CXCL1, andCXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NFκB-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NFκB-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes.

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Electronic ISSN: 1091-6490

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Protein–protein docking by fast generalized Fourier transforms on 5D rotational manifolds (2016)

Padhorny, Dzmitry ; Kazennov, Andrey ; Zerbe, Brandon S. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2016; 113(30): E4286-E4293. Published 2016 Jul 13. doi: 10.1073/pnas.1603929113.

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Publication Date: 2016-07-13

Description: Energy evaluation using fast Fourier transforms (FFTs) enables sampling billions of putative complex structures and hence revolutionized rigid protein–protein docking. However, in current methods, efficient acceleration is achieved only in either the translational or the rotational subspace. Developing an efficient and accurate docking method that expands FFT-based sampling to five rotational coordinates is an extensively studied but still unsolved problem. The algorithm presented here retains the accuracy of earlier methods but yields at least 10-fold speedup. The improvement is due to two innovations. First, the search space is treated as the product manifold SO(3)×(SO(3)∖S1), where SO(3) is the rotation group representing the space of the rotating ligand, and (SO(3)∖S1) is the space spanned by the two Euler angles that define the orientation of the vector from the center of the fixed receptor toward the center of the ligand. This representation enables the use of efficient FFT methods developed for SO(3). Second, we select the centers of highly populated clusters of docked structures, rather than the lowest energy conformations, as predictions of the complex, and hence there is no need for very high accuracy in energy evaluation. Therefore, it is sufficient to use a limited number of spherical basis functions in the Fourier space, which increases the efficiency of sampling while retaining the accuracy of docking results. A major advantage of the method is that, in contrast to classical approaches, increasing the number of correlation function terms is computationally inexpensive, which enables using complex energy functions for scoring.

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Electronic ISSN: 1091-6490

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Retrading, production, and asset market performance (2015)

Gjerstad, Steven D. ; Porter, David ; Smith, Vernon L. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(47): 14557-14562. Published 2015 Nov 09. doi: 10.1073/pnas.1517038112.

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Publication Date: 2015-11-09

Description: Prior studies have shown that traders quickly converge to the price–quantity equilibrium in markets for goods that are immediately consumed, but they produce speculative price bubbles in resalable asset markets. We present a stock-flow model of durable assets in which the existing stock of assets is subject to depreciation and producers may produce additional units of the asset. In our laboratory experiments inexperienced consumers who can resell their units disregard the consumption value of the assets and compete vigorously with producers, depressing prices and production. Consumers who have first participated in experiments without resale learn to heed their consumption values and, when they are given the option to resell, trade at equilibrium prices. Reproducibility is therefore the most natural and most effective treatment for suppression of bubbles in asset market experiments.

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Atmosphere–ocean oxygen and productivity dynamics during early animal radiations (2019)

Dahl, Tais W. ; Connelly, James N. ; Li, Da ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2019; 116(39): 19352-19361. Published 2019 Sep 09. doi: 10.1073/pnas.1901178116.

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Publication Date: 2019-09-09

Description: The proliferation of large, motile animals 540 to 520 Ma has been linked to both rising and declining O2 levels on Earth. To explore this conundrum, we reconstruct the global extent of seafloor oxygenation at approximately submillion-year resolution based on uranium isotope compositions of 187 marine carbonates samples from China, Siberia, and Morocco, and simulate O2 levels in the atmosphere and surface oceans using a mass balance model constrained by carbon, sulfur, and strontium isotopes in the same sedimentary successions. Our results point to a dynamically viable and highly variable state of atmosphere–ocean oxygenation with 2 massive expansions of seafloor anoxia in the aftermath of a prolonged interval of declining atmospheric pO2 levels. Although animals began diversifying beforehand, there were relatively few new appearances during these dramatic fluctuations in seafloor oxygenation. When O2 levels again rose, it occurred in concert with predicted high rates of photosynthetic production, both of which may have fueled more energy to predators and their armored prey in the evolving marine ecosystem.

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Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma (2019)

Porter, Rebecca L. ; Magnus, Neelima K. C. ; Thapar, Vishal ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2019; 116(52): 26835-26845. Published 2019 Dec 16. doi: 10.1073/pnas.1914915116.

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Publication Date: 2019-12-16

Description: Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials.

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Scaffold subunits support associated subunit assembly in the Chlamydomonas ciliary nexin–dynein regulatory complex (2019)

Gui, Long ; Song, Kangkang ; Tritschler, Douglas ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2019; 116(46): 23152-23162. Published 2019 Oct 28. doi: 10.1073/pnas.1910960116.

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Publication Date: 2019-10-28

Description: The nexin–dynein regulatory complex (N-DRC) in motile cilia and flagella functions as a linker between neighboring doublet microtubules, acts to stabilize the axonemal core structure, and serves as a central hub for the regulation of ciliary motility. Although the N-DRC has been studied extensively using genetic, biochemical, and structural approaches, the precise arrangement of the 11 (or more) N-DRC subunits remains unknown. Here, using cryo-electron tomography, we have compared the structure of Chlamydomonas wild-type flagella to that of strains with specific DRC subunit deletions or rescued strains with tagged DRC subunits. Our results show that DRC7 is a central linker subunit that helps connect the N-DRC to the outer dynein arms. DRC11 is required for the assembly of DRC8, and DRC8/11 form a subcomplex in the proximal lobe of the linker domain that is required to form stable contacts to the neighboring B-tubule. Gold labeling of tagged subunits determines the precise locations of the previously ambiguous N terminus of DRC4 and C terminus of DRC5. DRC4 is now shown to contribute to the core scaffold of the N-DRC. Our results reveal the overall architecture of N-DRC, with the 3 subunits DRC1/2/4 forming a core complex that serves as the scaffold for the assembly of the “functional subunits,” namely DRC3/5–8/11. These findings shed light on N-DRC assembly and its role in regulating flagellar beating.

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Enterotoxigenic E. coli virulence gene regulation in human infections (2018)

Crofts, Alexander A. ; Giovanetti, Simone M. ; Rubin, Erica J. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(38): E8968-E8976. Published 2018 Aug 20. doi: 10.1073/pnas.1808982115.

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Publication Date: 2018-08-20

Description: Enterotoxigenic Escherichia coli (ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other hallmarks of the intestinal tract, such as low oxygen availability, have not been examined. Further, determining how ETEC integrates these signals in the complex host environment is challenging. To address this, we characterized ETEC’s response to the human host using samples from a controlled human infection model. We found ETEC senses environmental oxygen to globally influence virulence factor expression via the oxygen-sensitive transcriptional regulator fumarate and nitrate reduction (FNR) regulator. In vitro anaerobic growth replicates the in vivo virulence factor expression profile, and deletion of fnr in ETEC strain H10407 results in a significant increase in expression of all classical virulence factors, including the colonization factor antigen I (CFA/I) adhesin operon and both heat-stable and heat-labile enterotoxins. These data depict a model of ETEC infection where FNR activity can globally influence virulence gene expression, and therefore proximity to the oxygenated zone bordering intestinal epithelial cells likely influences ETEC virulence gene expression in vivo. Outside of the host, ETEC biofilms are associated with seasonal ETEC epidemics, and we find FNR is a regulator of biofilm production. Together these data suggest FNR-dependent oxygen sensing in ETEC has implications for human infection inside and outside of the host.

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Pulcherrimin formation controls growth arrest of the Bacillus subtilis biofilm (2019)

Arnaouteli, Sofia ; Matoz-Fernandez, D. A. ; Porter, Michael ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2019; 116(27): 13553-13562. Published 2019 Jun 19. doi: 10.1073/pnas.1903982116.

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Publication Date: 2019-06-19

Description: Biofilm formation by Bacillus subtilis is a communal process that culminates in the formation of architecturally complex multicellular communities. Here we reveal that the transition of the biofilm into a nonexpanding phase constitutes a distinct step in the process of biofilm development. Using genetic analysis we show that B. subtilis strains lacking the ability to synthesize pulcherriminic acid form biofilms that sustain the expansion phase, thereby linking pulcherriminic acid to growth arrest. However, production of pulcherriminic acid is not sufficient to block expansion of the biofilm. It needs to be secreted into the extracellular environment where it chelates Fe3+ from the growth medium in a nonenzymatic reaction. Utilizing mathematical modeling and a series of experimental methodologies we show that when the level of freely available iron in the environment drops below a critical threshold, expansion of the biofilm stops. Bioinformatics analysis allows us to identify the genes required for pulcherriminic acid synthesis in other Firmicutes but the patchwork presence both within and across closely related species suggests loss of these genes through multiple independent recombination events. The seemingly counterintuitive self-restriction of growth led us to explore if there were any benefits associated with pulcherriminic acid production. We identified that pulcherriminic acid producers can prevent invasion by neighboring communities through the generation of an “iron-free” zone, thereby addressing the paradox of pulcherriminic acid production by B. subtilis.

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Extant fold-switching proteins are widespread (2018)

Porter, Lauren L. ; Looger, Loren L.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(23): 5968-5973. Published 2018 May 21. doi: 10.1073/pnas.1800168115.

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Publication Date: 2018-05-21

Description: A central tenet of biology is that globular proteins have a unique 3D structure under physiological conditions. Recent work has challenged this notion by demonstrating that some proteins switch folds, a process that involves remodeling of secondary structure in response to a few mutations (evolved fold switchers) or cellular stimuli (extant fold switchers). To date, extant fold switchers have been viewed as rare byproducts of evolution, but their frequency has been neither quantified nor estimated. By systematically and exhaustively searching the Protein Data Bank (PDB), we found ∼100 extant fold-switching proteins. Furthermore, we gathered multiple lines of evidence suggesting that these proteins are widespread in nature. Based on these lines of evidence, we hypothesized that the frequency of extant fold-switching proteins may be underrepresented by the structures in the PDB. Thus, we sought to identify other putative extant fold switchers with only one solved conformation. To do this, we identified two characteristic features of our ∼100 extant fold-switching proteins, incorrect secondary structure predictions and likely independent folding cooperativity, and searched the PDB for other proteins with similar features. Reassuringly, this method identified dozens of other proteins in the literature with indication of a structural change but only one solved conformation in the PDB. Thus, we used it to estimate that 0.5–4% of PDB proteins switch folds. These results demonstrate that extant fold-switching proteins are likely more common than the PDB reflects, which has implications for cell biology, genomics, and human health.

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Gold–silica quantum rattles for multimodal imaging and therapy (2015)

Hembury, Mathew ; Chiappini, Ciro ; Bertazzo, Sergio ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(7): 1959-1964. Published 2015 Feb 04. doi: 10.1073/pnas.1419622112.

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Publication Date: 2015-02-04

Description: Gold quantum dots exhibit distinctive optical and magnetic behaviors compared with larger gold nanoparticles. However, their unfavorable interaction with living systems and lack of stability in aqueous solvents has so far prevented their adoption in biology and medicine. Here, a simple synthetic pathway integrates gold quantum dots within a mesoporous silica shell, alongside larger gold nanoparticles within the shell’s central cavity. This “quantum rattle” structure is stable in aqueous solutions, does not elicit cell toxicity, preserves the attractive near-infrared photonics and paramagnetism of gold quantum dots, and enhances the drug-carrier performance of the silica shell. In vivo, the quantum rattles reduced tumor burden in a single course of photothermal therapy while coupling three complementary imaging modalities: near-infrared fluorescence, photoacoustic, and magnetic resonance imaging. The incorporation of gold within the quantum rattles significantly enhanced the drug-carrier performance of the silica shell. This innovative material design based on the mutually beneficial interaction of gold and silica introduces the use of gold quantum dots for imaging and therapeutic applications.

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