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Dive into the research topics where Michael G. Roth is active.

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Featured researches published by Michael G. Roth.


Nature Chemical Biology | 2009

Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer

Baozhi Chen; Michael E. Dodge; Wei Tang; Jianming Lu; Zhiqiang Ma; Chih Wei Fan; Shuguang Wei; Wayne Hao; Jessica A. Kilgore; Noelle S. Williams; Michael G. Roth; James F. Amatruda; Chuo Chen; Lawrence Lum

SUMMARY The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two novel classes of small molecules that disrupt Wnt pathway responses - whereas one class inhibits the activity of Porcupine (Porcn), a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, suppressors of Wnt/β-catenin pathway activity. With these small molecules we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/β-catenin pathway response in vivo, and establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.


The EMBO Journal | 1997

Interaction of influenza virus haemagglutinin with sphingolipid–cholesterol membrane domains via its transmembrane domain

Peter Scheiffele; Michael G. Roth; Kai Simons

Sphingolipid–cholesterol rafts are microdomains in biological membranes with liquid‐ordered phase properties which are implicated in membrane traffic and signalling events. We have used influenza virus haemagglutinin (HA) as a model protein to analyse the interaction of transmembrane proteins with these microdomains. Here we demonstrate that raft association is an intrinsic property encoded in the protein. Mutant HA molecules with foreign transmembrane domain (TMD) sequences lose their ability to associate with the lipid microdomains, and mutations in the HA TMD reveal a requirement for hydrophobic residues in contact with the exoplasmic leaflet of the membrane. We also provide experimental evidence that cholesterol is critically required for association of proteins with lipid rafts. Our data suggest that the binding to specific membrane domains can be encoded in transmembrane proteins and that this information will be used for polarized sorting and signal transduction processes.


Cell | 2003

Phosphatidylinositol 4 Phosphate Regulates Targeting of Clathrin Adaptor AP-1 Complexes to the Golgi

Ying Jie Wang; Jing Wang; Hui Qiao Sun; Manuel Martinez; Yu Xiao Sun; Eric Macia; Tomas Kirchhausen; Joseph P. Albanesi; Michael G. Roth; Helen L. Yin

Phosphatidylinositol 4 phosphate [PI(4)P] is essential for secretion in yeast, but its role in mammalian cells is unclear. Current paradigms propose that PI(4)P acts primarily as a precursor to phosphatidylinositol 4,5 bisphosphate (PIP2), an important plasma membrane regulator. We found that PI(4)P is enriched in the mammalian Golgi, and used RNA interference (RNAi) of PI4KIIalpha, a Golgi resident phosphatidylinositol 4 kinase, to determine whether PI(4)P directly regulates the Golgi. PI4KIIalpha RNAi decreases Golgi PI(4)P, blocks the recruitment of clathrin adaptor AP-1 complexes to the Golgi, and inhibits AP-1-dependent functions. This AP-1 binding defect is rescued by adding back PI(4)P. In addition, purified AP-1 binds PI(4)P, and anti-PI(4)P inhibits the in vitro recruitment of cytosolic AP-1 to normal cellular membranes. We propose that PI4KIIalpha establishes the Golgis unique lipid-defined organelle identity by generating PI(4)P-rich domains that specify the docking of the AP-1 coat machinery.


Nature | 2007

Synthetic lethal screen identification of chemosensitizer loci in cancer cells

Angelique W. Whitehurst; Brian O. Bodemann; Jessica Cardenas; Deborah A. Ferguson; Luc Girard; Michael Peyton; John D. Minna; Carolyn H. Michnoff; Weihua Hao; Michael G. Roth; Xian Jin Xie; Michael A. White

Abundant evidence suggests that a unifying principle governing the molecular pathology of cancer is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis. Anomalous proteins engaged in support of this tumorigenic regulatory environment most probably represent optimal intervention targets in a heterogeneous population of cancer cells. The advent of RNA-mediated interference (RNAi)-based functional genomics provides the opportunity to derive unbiased comprehensive collections of validated gene targets supporting critical biological systems outside the framework of preconceived notions of mechanistic relationships. We have combined a high-throughput cell-based one-well/one-gene screening platform with a genome-wide synthetic library of chemically synthesized small interfering RNAs for systematic interrogation of the molecular underpinnings of cancer cell chemoresponsiveness. NCI-H1155, a human non-small-cell lung cancer line, was employed in a paclitaxel-dependent synthetic lethal screen designed to identify gene targets that specifically reduce cell viability in the presence of otherwise sublethal concentrations of paclitaxel. Using a stringent objective statistical algorithm to reduce false discovery rates below 5%, we isolated a panel of 87 genes that represent major focal points of the autonomous response of cancer cells to the abrogation of microtubule dynamics. Here we show that several of these targets sensitize lung cancer cells to paclitaxel concentrations 1,000-fold lower than otherwise required for a significant response, and we identify mechanistic relationships between cancer-associated aberrant gene expression programmes and the basic cellular machinery required for robust mitotic progression.


Science | 2008

Targeting QseC Signaling and Virulence for Antibiotic Development

David A. Rasko; Cristiano G. Moreira; De Run Li; Nicola C. Reading; Jennifer M. Ritchie; Matthew K. Waldor; Noelle S. Williams; Ronald Taussig; Shuguang Wei; Michael G. Roth; David T. Hughes; Jason F. Huntley; Maggy Fina; John R. Falck; Vanessa Sperandio

Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.


Nature | 2011

Image-Based Genome-Wide siRNA Screen Identifies Selective Autophagy Factors

Anthony Orvedahl; Rhea Sumpter; Guanghua Xiao; Aylwin Ng; Zhongju Zou; Yi Tang; Masahiro Narimatsu; Christopher Gilpin; Qihua Sun; Michael G. Roth; Christian V. Forst; Jeffrey L. Wrana; Ying Zhang; Katherine Luby-Phelps; Ramnik J. Xavier; Yang Xie; Beth Levine

Selective autophagy involves the recognition and targeting of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens for lysosomal destruction. Yeast genetic screens have identified proteins required for different forms of selective autophagy, including cytoplasm-to-vacuole targeting, pexophagy and mitophagy, and mammalian genetic screens have identified proteins required for autophagy regulation. However, there have been no systematic approaches to identify molecular determinants of selective autophagy in mammalian cells. Here, to identify mammalian genes required for selective autophagy, we performed a high-content, image-based, genome-wide small interfering RNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes. We identified 141 candidate genes required for viral autophagy, which were enriched for cellular pathways related to messenger RNA processing, interferon signalling, vesicle trafficking, cytoskeletal motor function and metabolism. Ninety-six of these genes were also required for Parkin-mediated mitophagy, indicating that common molecular determinants may be involved in autophagic targeting of viral nucleocapsids and autophagic targeting of damaged mitochondria. Murine embryonic fibroblasts lacking one of these gene products, the C2-domain containing protein, SMURF1, are deficient in the autophagosomal targeting of Sindbis and herpes simplex viruses and in the clearance of damaged mitochondria. Moreover, SMURF1-deficient mice accumulate damaged mitochondria in the heart, brain and liver. Thus, our study identifies candidate determinants of selective autophagy, and defines SMURF1 as a newly recognized mediator of both viral autophagy and mitophagy.


Current Biology | 1997

Phosphatidic acid formation by phospholipase D is required for transport from the endoplasmic reticulum to the Golgi complex

Kun Bi; Michael G. Roth; Nicholas T. Ktistakis

BACKGROUND Lipid molecules may play a regulatory role in the secretory pathway of mammals and yeast. The lipid hydrolase phospholipase D (PLD) is one candidate for mediating regulation of secretion, based on the location of this enzyme and its requirements for activation. RESULTS We found that primary alcohols, which block formation of phosphatidic acid (PA) by PLD, inhibited the transport of two different viral glycoproteins from the endoplasmic reticulum to the Golgi complex in Chinese hamster ovary cells. Corresponding secondary alcohols, which are much less potent in blocking PA formation, were also less effective in blocking transport of the glycoproteins. The block in glycoprotein transport imposed by primary alcohols was reversed when PA, in the form of liposomes, was exogenously supplied to the culture medium. CONCLUSIONS We suggest that the earliest site of regulation of membrane transport by PLD is within the intermediate compartment between the endoplasmic reticulum and the Golgi complex.


Cell | 1988

A single amino acid change in the cytoplasmic domain allows the influenza virus hemagglutinin to be endocytosed through coated pits

Janette Lazarovits; Michael G. Roth

Through site-specific mutagenesis, three of the ten amino acids of the cytoplasmic domain of the influenza virus hemagglutinin (HA) were individually changed to tyrosines. None of these changes had significant effect on the rate of export, the rate of folding, or the antigenicity of the mutant HAs. However, one of these mutations, substituting tyrosine for cysteine at amino acid 543, changed HA from a protein that was endocytosed at a very low rate to a protein that readily entered coated pits, was internalized, and apparently recycled to the cell surface. Replacement of cysteine 543 with phenylalanine or serine did not increase the rate of internalization of HA. Phosphorylation of the mutant HA bearing a tyrosine at position 543 was not detected. These results indicate a specific and local role for the tyrosine introduced into the cytoplasmic domain of HA that is necessary for interaction of the protein with coated pits.


Journal of Cell Biology | 2003

Phosphatidylinositol phosphate 5-kinase Iβ recruits AP-2 to the plasma membrane and regulates rates of constitutive endocytosis

David Padrón; Ying Jie Wang; Masaya Yamamoto; Helen L. Yin; Michael G. Roth

Overexpression of phosphatidylinositol phosphate 5-kinase (PIP5KI) isoforms α, β, or γ in CV-1 cells increased phosphatidylinositol 4,5-bisphosphate (PIP2) levels by 35, 180, and 0%, respectively. Endocytosis of transferrin receptors, association of AP-2 proteins with membranes, and the number of clathrin-coated pits at the plasma membrane increased when PIP2 increased. When expression of PIP5KIβ was inhibited with small interference RNA in HeLa cells, expression of PIP5KIα was also reduced slightly, but PIP5KIγ expression was increased. PIP2 levels and internalization of transferrin receptors dropped 50% in these cells; thus, PIP5KIγ could not compensate for loss of PIP5KIβ. When expression of PIP5KIα was reduced, expression of both PIP5KIβ and PIP5KIγ increased and PIP2 levels did not change. A similar increase of PIP5KIα and PIP5KIβ occurred when PIP5KIγ was inhibited. These results indicate that constitutive endocytosis in CV-1 and HeLa cells requires (and may be regulated by) PIP2 produced primarily by PIP5KIβ.


Proceedings of the National Academy of Sciences of the United States of America | 2008

A genome-wide RNAi screen for Wnt/β-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer

Wei Tang; Michael E. Dodge; Deepika Gundapaneni; Carolyn H. Michnoff; Michael G. Roth; Lawrence Lum

The Wnt family of secreted proteins coordinate cell fate decision-making in a broad range of developmental and homeostatic contexts. Corruption of Wnt signal transduction pathways frequently results in degenerative diseases and cancer. We have used an iterative genome-wide screening strategy that employs multiple nonredundant RNAi reagents to identify mammalian genes that participate in Wnt/β-catenin pathway response. Among the genes that were assigned high confidence scores are two members of the TCF/LEF family of DNA-binding proteins that control the transcriptional output of the pathway. Surprisingly, we found that the presumed cancer-promoting gene TCF7L2 functions instead as a transcriptional repressor that restricts colorectal cancer (CRC) cell growth. Mutations in TCF7L2 identified from cancer genome sequencing efforts abolish its ability to function as a transcriptional regulator and result in increased CRC cell growth. We describe a growth-promoting transcriptional program that is likely activated in CRC tumors with compromised TCF7L2 function. Taken together, the results from our screen and studies focused on members of the TCF/LEF gene family refine our understanding of how aberrant Wnt pathway activation sustains CRC growth.

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Shuguang Wei

University of Texas Southwestern Medical Center

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Michael A. White

University of Texas Southwestern Medical Center

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John D. Minna

University of Texas Southwestern Medical Center

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Noelle S. Williams

University of Texas Southwestern Medical Center

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Roger H. Unger

University of Texas Southwestern Medical Center

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Adi F. Gazdar

University of Texas Southwestern Medical Center

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Bruce A. Posner

University of Texas Southwestern Medical Center

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Iryna Zubovych

University of Texas Southwestern Medical Center

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Jef K. De Brabander

University of Texas Southwestern Medical Center

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