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Davis Lab Publications

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Articles 1 - 30 of 38

Full-Text Articles in Molecular Biology

Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis Jun 2018

Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis

Davis Lab Publications

Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more ...


Hyper- And Hypo- Nutrition Studies Of The Hepatic Transcriptome And Epigenome Suggest That Pparα Regulates Anaerobic Glycolysis, Anthony R. Soltis, Shmulik Motola, Santiago Vernia, Christopher W. Ng, Norman J. Kennedy, Simona Dalin, Bryan J. Matthews, Roger J. Davis, Ernest Fraenkel Mar 2017

Hyper- And Hypo- Nutrition Studies Of The Hepatic Transcriptome And Epigenome Suggest That Pparα Regulates Anaerobic Glycolysis, Anthony R. Soltis, Shmulik Motola, Santiago Vernia, Christopher W. Ng, Norman J. Kennedy, Simona Dalin, Bryan J. Matthews, Roger J. Davis, Ernest Fraenkel

Davis Lab Publications

Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD), or a CR diet to compare and contrast the effects of these diets on mouse liver biology. We collected transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the ...


Suppression Of Ischemia In Arterial Occlusive Disease By Jnk-Promoted Native Collateral Artery Development, Kasmir Ramo, Koichi Sugamura, Siobhan M. Craige, John F. Keaney Jr., Roger J. Davis Aug 2016

Suppression Of Ischemia In Arterial Occlusive Disease By Jnk-Promoted Native Collateral Artery Development, Kasmir Ramo, Koichi Sugamura, Siobhan M. Craige, John F. Keaney Jr., Roger J. Davis

Davis Lab Publications

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive ...


Inflammation Mediated By Jnk In Myeloid Cells Promotes The Development Of Hepatitis And Hepatocellular Carcinoma, Myoung Souk Han, Tamera Barrett, Michael A. Brehm, Roger J. Davis Apr 2016

Inflammation Mediated By Jnk In Myeloid Cells Promotes The Development Of Hepatitis And Hepatocellular Carcinoma, Myoung Souk Han, Tamera Barrett, Michael A. Brehm, Roger J. Davis

Davis Lab Publications

The cJun NH2-terminal kinase (JNK) signaling pathway is required for the development of hepatitis and hepatocellular carcinoma. A role for JNK in liver parenchymal cells has been proposed, but more recent studies have implicated non-parenchymal liver cells as the relevant site of JNK signaling. Here, we tested the hypothesis that myeloid cells mediate this function of JNK. We show that mice with myeloid cell-specific JNK deficiency exhibit reduced hepatic inflammation and suppression of both hepatitis and hepatocellular carcinoma. These data identify myeloid cells as a site of pro-inflammatory signaling by JNK that can promote liver pathology. Targeting myeloid cells with ...


Fibroblast Growth Factor 21 Mediates Glycemic Regulation By Hepatic Jnk, Santiago Vernia, Julie Cavanagh-Kyros, Tamera Barrett, Cathy Tournier, Roger J. Davis Mar 2016

Fibroblast Growth Factor 21 Mediates Glycemic Regulation By Hepatic Jnk, Santiago Vernia, Julie Cavanagh-Kyros, Tamera Barrett, Cathy Tournier, Roger J. Davis

Davis Lab Publications

The cJun NH2-terminal kinase (JNK)-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK-signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including ...


Excitatory Transmission Onto Agrp Neurons Is Regulated By Cjun Nh2-Terminal Kinase 3 In Response To Metabolic Stress, Santiago Vernia, Caroline Morel, Joseph C. Madara, Julie Cavanagh-Kyros, Tamera Barrett, Kathryn O. Chase, Norman J. Kennedy, Dae Young Jung, Jason K. Kim, Neil Aronin, Richard A. Flavell, Bradford B. Lowell, Roger J. Davis Feb 2016

Excitatory Transmission Onto Agrp Neurons Is Regulated By Cjun Nh2-Terminal Kinase 3 In Response To Metabolic Stress, Santiago Vernia, Caroline Morel, Joseph C. Madara, Julie Cavanagh-Kyros, Tamera Barrett, Kathryn O. Chase, Norman J. Kennedy, Dae Young Jung, Jason K. Kim, Neil Aronin, Richard A. Flavell, Bradford B. Lowell, Roger J. Davis

Davis Lab Publications

The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These ...


Tead And Ap1 Coordinate Transcription And Motility, Xiangfan Liu, Huapeng Li, Mihir S. Rajurkar, Qi Li, Jennifer L. Cotton, Jianhong Ou, Lihua J. Zhu, Hira L. Goel, Arthur M. Mercurio, Joo-Seop Park, Roger J. Davis, Junhao Mao Feb 2016

Tead And Ap1 Coordinate Transcription And Motility, Xiangfan Liu, Huapeng Li, Mihir S. Rajurkar, Qi Li, Jennifer L. Cotton, Jianhong Ou, Lihua J. Zhu, Hira L. Goel, Arthur M. Mercurio, Joo-Seop Park, Roger J. Davis, Junhao Mao

Davis Lab Publications

The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we ...


Inactivation Of Nuclear Gsk3beta By Ser(389) Phosphorylation Promotes Lymphocyte Fitness During Dna Double-Strand Break Response, Tina M. Thornton, Pilar Delgado, Liang Chen, Beatriz Salas, Dimitry Krementsov, Miriam Fernandez, Santiago Vernia, Roger J. Davis, Ruth Heimann, Cory Teuscher, Michael S. Krangel, Almudena R. Ramiro, Mercedes Rincon Jan 2016

Inactivation Of Nuclear Gsk3beta By Ser(389) Phosphorylation Promotes Lymphocyte Fitness During Dna Double-Strand Break Response, Tina M. Thornton, Pilar Delgado, Liang Chen, Beatriz Salas, Dimitry Krementsov, Miriam Fernandez, Santiago Vernia, Roger J. Davis, Ruth Heimann, Cory Teuscher, Michael S. Krangel, Almudena R. Ramiro, Mercedes Rincon

Davis Lab Publications

Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclear whether this response is associated with distinct survival signals that protect T and B cells. Glycogen synthase kinase 3beta (GSK3beta) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3beta on Ser(389) by p38 MAPK (mitogen-activated protein kinase) is induced selectively by DSBs through ATM (ataxia telangiectasia mutated) as a unique mechanism to attenuate the ...


Presynaptic C-Jun N-Terminal Kinase 2 Regulates Nmda Receptor-Dependent Glutamate Release, Robert Nistico, Fulvio Florenzano, Dalila Mango, Caterina Ferraina, Massimo Grilli, Silvia Di Prisco, Annalisa Nobili, Stefania Saccucci, Marcello D'Amelio, Michela Morbin, Mario Marchi, Nicola B. Mercuri, Roger J. Davis, Anna Pittaluga, Marco Feligioni Mar 2015

Presynaptic C-Jun N-Terminal Kinase 2 Regulates Nmda Receptor-Dependent Glutamate Release, Robert Nistico, Fulvio Florenzano, Dalila Mango, Caterina Ferraina, Massimo Grilli, Silvia Di Prisco, Annalisa Nobili, Stefania Saccucci, Marcello D'Amelio, Michela Morbin, Mario Marchi, Nicola B. Mercuri, Roger J. Davis, Anna Pittaluga, Marco Feligioni

Davis Lab Publications

Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for ...


Quantitative Analysis Of App Axonal Transport In Neurons: Role Of Jip1 In Enhanced App Anterograde Transport, Kyoko Chiba, Masahiko Araseki, Keisuke Nozawa, Keiko Furukori, Yoichi Araki, Takahide Matsushima, Tadashi Nakaya, Saori Hata, Yuhki Saito, Seiichi Uchida, Yasushi Okada, Angus C. Nairn, Roger J. Davis, Tohru Yamamoto, Masataka Kinjo, Hidenori Taru, Toshiharu Suzuki Nov 2014

Quantitative Analysis Of App Axonal Transport In Neurons: Role Of Jip1 In Enhanced App Anterograde Transport, Kyoko Chiba, Masahiko Araseki, Keisuke Nozawa, Keiko Furukori, Yoichi Araki, Takahide Matsushima, Tadashi Nakaya, Saori Hata, Yuhki Saito, Seiichi Uchida, Yasushi Okada, Angus C. Nairn, Roger J. Davis, Tohru Yamamoto, Masataka Kinjo, Hidenori Taru, Toshiharu Suzuki

Davis Lab Publications

Alzheimer's beta-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity ( approximately 2.7 mum/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity ( approximately 1.83 mum/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b ...


Mnk2 Alternative Splicing Modulates The P38-Mapk Pathway And Impacts Ras-Induced Transformation, Avraham Maimon, Maxim Mogilevsky, Asaf Shilo, Regina Golan-Gerstl, Akram Obiedat, Vered Ben-Hur, Ilana Lebenthal-Loinger, Ilan Stein, Reuven Reich, Jonah Beenstock, Eldar Zehorai, Claus L. Andersen, Kasper Thorsen, Torben F. Orntoft, Roger J. Davis, Ben Davidson, David Mu, Rotem Karni Apr 2014

Mnk2 Alternative Splicing Modulates The P38-Mapk Pathway And Impacts Ras-Induced Transformation, Avraham Maimon, Maxim Mogilevsky, Asaf Shilo, Regina Golan-Gerstl, Akram Obiedat, Vered Ben-Hur, Ilana Lebenthal-Loinger, Ilan Stein, Reuven Reich, Jonah Beenstock, Eldar Zehorai, Claus L. Andersen, Kasper Thorsen, Torben F. Orntoft, Roger J. Davis, Ben Davidson, David Mu, Rotem Karni

Davis Lab Publications

The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38alpha-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate ...


Analysis Of In Vitro Insulin-Resistance Models And Their Physiological Relevance To In Vivo Diet-Induced Adipose Insulin Resistance, Kinyui Alice Lo, Adam Labadorf, Norman J. Kennedy, Myoung Souk Han, Yoon Sing Yap, Bryan Matthews, Xiaofeng Xin, Lei Sun, Roger J. Davis, Harvey F. Lodish, Ernest Fraenkel Oct 2013

Analysis Of In Vitro Insulin-Resistance Models And Their Physiological Relevance To In Vivo Diet-Induced Adipose Insulin Resistance, Kinyui Alice Lo, Adam Labadorf, Norman J. Kennedy, Myoung Souk Han, Yoon Sing Yap, Bryan Matthews, Xiaofeng Xin, Lei Sun, Roger J. Davis, Harvey F. Lodish, Ernest Fraenkel

Davis Lab Publications

Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-alpha, hypoxia, dexamethasone, high insulin, and a combination of TNF-alpha and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment ...


Jnk Regulates Compliance-Induced Adherens Junctions Formation In Epithelial Cells And Tissues, Hui You, Roshan M. Padmashali, Aishwarya Ranganathan, Pedro Lei, Nomeda Girnius, Roger J. Davis, Stelios T. Andreadis Jun 2013

Jnk Regulates Compliance-Induced Adherens Junctions Formation In Epithelial Cells And Tissues, Hui You, Roshan M. Padmashali, Aishwarya Ranganathan, Pedro Lei, Nomeda Girnius, Roger J. Davis, Stelios T. Andreadis

Davis Lab Publications

We demonstrate that c-Jun N-terminal kinase (JNK) responds to substrate stiffness and regulates adherens junction (AJ) formation in epithelial cells in 2D cultures and in 3D tissues in vitro and in vivo. Rigid substrates led to JNK activation and AJ disassembly, whereas soft matrices suppressed JNK activity leading to AJ formation. Expression of constitutively active JNK (MKK7-JNK1) induced AJ dissolution even on soft substrates, whereas JNK knockdown (using shJNK) induced AJ formation even on hard substrates. In human epidermis, basal cells expressed phosphorylated JNK but lacked AJ, whereas suprabasal keratinocytes contained strong AJ but lacked phosphorylated JNK. AJ formation was ...


Eukaryotic Elongation Factor 2 Controls Tnf-Alpha Translation In Lps-Induced Hepatitis, Barbara Gonzalez-Teran, Jose R. Cortes, Elisa Manieri, Nuria Matesanz, Angeles Verdugo, Maria E. Rodriguez, Agueda Gonzalez-Rodriguez, Angela M. Valverde, Pilar Martin, Roger J. Davis, Guadalupe Sabio Jan 2013

Eukaryotic Elongation Factor 2 Controls Tnf-Alpha Translation In Lps-Induced Hepatitis, Barbara Gonzalez-Teran, Jose R. Cortes, Elisa Manieri, Nuria Matesanz, Angeles Verdugo, Maria E. Rodriguez, Agueda Gonzalez-Rodriguez, Angela M. Valverde, Pilar Martin, Roger J. Davis, Guadalupe Sabio

Davis Lab Publications

Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-alpha. TNF-alpha is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-alpha expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38gamma/delta MAPK proteins is required for the elongation of nascent TNF-alpha protein in macrophages. The MKK3/6-p38gamma/delta pathway ...


Jnk And Pten Cooperatively Control The Development Of Invasive Adenocarcinoma Of The Prostate, Anette Hubner, David J. Mulholland, Claire L. Standen, Maria Karasarides, Julie Cavanagh-Kyros, Tamera Barrett, Hongbo Chi, Dale Greiner, Cathy Tournier, Charles L. Sawyers, Richard A. Flavell, Hong Wu, Roger J. Davis Jul 2012

Jnk And Pten Cooperatively Control The Development Of Invasive Adenocarcinoma Of The Prostate, Anette Hubner, David J. Mulholland, Claire L. Standen, Maria Karasarides, Julie Cavanagh-Kyros, Tamera Barrett, Hongbo Chi, Dale Greiner, Cathy Tournier, Charles L. Sawyers, Richard A. Flavell, Hong Wu, Roger J. Davis

Davis Lab Publications

The c-Jun NH(2)-terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (DeltaJnk DeltaPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (DeltaPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (DeltaMkk4 DeltaMkk7 DeltaPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an ...


Retinol-Binding Protein 4 Inhibits Insulin Signaling In Adipocytes By Inducing Proinflammatory Cytokines In Macrophages Through A C-Jun N-Terminal Kinase- And Toll-Like Receptor 4-Dependent And Retinol-Independent Mechanism, Julie Norseen, Tetsuya Hosooka, Ann Hammarstedt, Mark M. Yore, Shashi Kant, Pratik Aryal, Urban A. Kiernan, David A. Phillips, Hiroshi Maruyama, Bettina J. Kraus, Anny Usheva, Roger J. Davis, Ulf Smith, Barbara B. Kahn May 2012

Retinol-Binding Protein 4 Inhibits Insulin Signaling In Adipocytes By Inducing Proinflammatory Cytokines In Macrophages Through A C-Jun N-Terminal Kinase- And Toll-Like Receptor 4-Dependent And Retinol-Independent Mechanism, Julie Norseen, Tetsuya Hosooka, Ann Hammarstedt, Mark M. Yore, Shashi Kant, Pratik Aryal, Urban A. Kiernan, David A. Phillips, Hiroshi Maruyama, Bettina J. Kraus, Anny Usheva, Roger J. Davis, Ulf Smith, Barbara B. Kahn

Davis Lab Publications

Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and liver. Serum RBP4 levels correlate highly with insulin resistance, other metabolic syndrome factors, and cardiovascular disease. Elevated serum RBP4 causes insulin resistance, but the molecular mechanisms are unknown. Here we show that RBP4 induces expression of proinflammatory cytokines in mouse and human macrophages and thereby indirectly inhibits insulin signaling in cocultured adipocytes. This occurs through activation of c-Jun N-terminal protein kinase (JNK) and Toll-like receptor 4 (TLR4) pathways independent of the RBP4 receptor, STRA6. RBP4 effects are markedly attenuated in JNK1-/- JNK2-/- macrophages and TLR4- ...


The Loss Of C-Jun N-Terminal Protein Kinase Activity Prevents The Amyloidogenic Cleavage Of Amyloid Precursor Protein And The Formation Of Amyloid Plaques In Vivo, Sonia Mazzitelli, Ping Xu, Isidre Ferrer, Roger J. Davis, Cathy Tournier Nov 2011

The Loss Of C-Jun N-Terminal Protein Kinase Activity Prevents The Amyloidogenic Cleavage Of Amyloid Precursor Protein And The Formation Of Amyloid Plaques In Vivo, Sonia Mazzitelli, Ping Xu, Isidre Ferrer, Roger J. Davis, Cathy Tournier

Davis Lab Publications

Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-beta (Abeta), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant Abeta production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to ...


Mlk3 Regulates Bone Development Downstream Of The Faciogenital Dysplasia Protein Fgd1 In Mice, Weiguo Zou, Matthew B. Greenblatt, Jae-Hyuck Shim, Shashi Kant, Bo Zhai, Sutada Lotinun, Nicholas Brady, Dorothy Zhang Hu, Steven P. Gygi, Roland Baron, Roger J. Davis, Dallas Jones, Laurie H. Glimcher Nov 2011

Mlk3 Regulates Bone Development Downstream Of The Faciogenital Dysplasia Protein Fgd1 In Mice, Weiguo Zou, Matthew B. Greenblatt, Jae-Hyuck Shim, Shashi Kant, Bo Zhai, Sutada Lotinun, Nicholas Brady, Dorothy Zhang Hu, Steven P. Gygi, Roland Baron, Roger J. Davis, Dallas Jones, Laurie H. Glimcher

Davis Lab Publications

Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate ...


Tnf-Stimulated Map Kinase Activation Mediated By A Rho Family Gtpase Signaling Pathway, Shashi Kant, Wojciech Swat, Sheng Zhang, Zhong-Yin Zhang, Benjamin G. Neel, Richard A. Flavell, Roger J. Davis Oct 2011

Tnf-Stimulated Map Kinase Activation Mediated By A Rho Family Gtpase Signaling Pathway, Shashi Kant, Wojciech Swat, Sheng Zhang, Zhong-Yin Zhang, Benjamin G. Neel, Richard A. Flavell, Roger J. Davis

Davis Lab Publications

The biological response to tumor necrosis factor (TNF) involves activation of MAP kinases. Here we report a mechanism of MAP kinase activation by TNF that is mediated by the Rho GTPase family members Rac/Cdc42. This signaling pathway requires Src-dependent activation of the guanosine nucleotide exchange factor Vav, activation of Rac/Cdc42, and the engagement of the Rac/Cdc42 interaction site (CRIB motif) on mixed-lineage protein kinases (MLKs). We show that this pathway is essential for full MAP kinase activation during the response to TNF. Moreover, this MLK pathway contributes to inflammation in vivo.


Requirement Of C-Jun Nh(2)-Terminal Kinase For Ras-Initiated Tumor Formation, Cristina Arrigo Cellurale, Guadalupe Sabio, Norman J. Kennedy, Madhumita Das, Marissa Bylsma, Peter Sandy, Tyler Jacks, Roger J. Davis Apr 2011

Requirement Of C-Jun Nh(2)-Terminal Kinase For Ras-Initiated Tumor Formation, Cristina Arrigo Cellurale, Guadalupe Sabio, Norman J. Kennedy, Madhumita Das, Marissa Bylsma, Peter Sandy, Tyler Jacks, Roger J. Davis

Davis Lab Publications

The c-Jun NH(2)-terminal kinase (JNK) signal transduction pathway causes increased gene expression mediated, in part, by members of the activating transcription factor protein (AP1) group. JNK is therefore implicated in the regulation of cell growth and cancer. To test the role of JNK in Ras-induced tumor formation, we examined the effect of compound ablation of the ubiquitously expressed genes Jnk1 plus Jnk2. We report that JNK is required for Ras-induced transformation of p53-deficient primary cells in vitro. Moreover, JNK is required for lung tumor development caused by mutational activation of the endogenous KRas gene in vivo. Together, these ...


The Role Of Jnk In The Development Of Hepatocellular Carcinoma, Madhumita Das, David S. Garlick, Dale Greiner, Roger J. Davis Mar 2011

The Role Of Jnk In The Development Of Hepatocellular Carcinoma, Madhumita Das, David S. Garlick, Dale Greiner, Roger J. Davis

Davis Lab Publications

The cJun NH(2)-terminal kinase (JNK) signal transduction pathway has been implicated in the growth of carcinogen-induced hepatocellular carcinoma. However, the mechanism that accounts for JNK-regulated tumor growth is unclear. Here we demonstrate that compound deficiency of the two ubiquitously expressed JNK isoforms (JNK1 and JNK2) in hepatocytes does not prevent hepatocellular carcinoma development. Indeed, JNK deficiency in hepatocytes increased the tumor burden. In contrast, compound JNK deficiency in hepatocytes and nonparenchymal cells reduced both hepatic inflammation and tumorigenesis. These data indicate that JNK plays a dual role in the development of hepatocellular carcinoma. JNK promotes an inflammatory hepatic ...


Jnk Regulates Foxo-Dependent Autophagy In Neurons, Ping Xu, Madhumita Das, Judith Reilly, Roger J. Davis Feb 2011

Jnk Regulates Foxo-Dependent Autophagy In Neurons, Ping Xu, Madhumita Das, Judith Reilly, Roger J. Davis

Davis Lab Publications

The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.


Hippocampal C-Jun-N-Terminal Kinases Serve As Negative Regulators Of Associative Learning, Tessi Sherrin, Thomas Blank, Cathrin Hippel, Martin Rayner, Roger J. Davis, Cedomir Todorovic Oct 2010

Hippocampal C-Jun-N-Terminal Kinases Serve As Negative Regulators Of Associative Learning, Tessi Sherrin, Thomas Blank, Cathrin Hippel, Martin Rayner, Roger J. Davis, Cedomir Todorovic

Davis Lab Publications

In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 mum) or D-JNKI1 (8 mum) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 mug/mul), a potent JNKs activator, mimicked ...


Requirement Of Jip1-Mediated C-Jun N-Terminal Kinase Activation For Obesity-Induced Insulin Resistance, Caroline Morel, Claire L. Standen, Dae Young Jung, Susan Gray, Helena Ong, Richard A. Flavell, Jason K. Kim, Roger J. Davis Oct 2010

Requirement Of Jip1-Mediated C-Jun N-Terminal Kinase Activation For Obesity-Induced Insulin Resistance, Caroline Morel, Claire L. Standen, Dae Young Jung, Susan Gray, Helena Ong, Richard A. Flavell, Jason K. Kim, Roger J. Davis

Davis Lab Publications

The c-Jun NH(2)-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr(103) replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat ...


The P38 Mapk Pathway Is Essential For Skeletogenesis And Bone Homeostasis In Mice, Matthew B. Greenblatt, Jae-Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger J. Davis, Laurie H. Glimcher Jul 2010

The P38 Mapk Pathway Is Essential For Skeletogenesis And Bone Homeostasis In Mice, Matthew B. Greenblatt, Jae-Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger J. Davis, Laurie H. Glimcher

Davis Lab Publications

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known ...


Distinct Roles Of C-Jun N-Terminal Kinase Isoforms In Neurite Initiation And Elongation During Axonal Regeneration, Monia Barnat, Herve Enslen, Friedrich Propst, Roger J. Davis, Sylvia Soares, Fatiha Nothias Jun 2010

Distinct Roles Of C-Jun N-Terminal Kinase Isoforms In Neurite Initiation And Elongation During Axonal Regeneration, Monia Barnat, Herve Enslen, Friedrich Propst, Roger J. Davis, Sylvia Soares, Fatiha Nothias

Davis Lab Publications

c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ...


Microtubule Stabilization By Bone Morphogenetic Protein Receptor-Mediated Scaffolding Of C-Jun N-Terminal Kinase Promotes Dendrite Formation, Monika Podkowa, Xin Zhao, Chi-Wing Chow, Eleanor T. Coffey, Roger J. Davis, Liliana Attisano May 2010

Microtubule Stabilization By Bone Morphogenetic Protein Receptor-Mediated Scaffolding Of C-Jun N-Terminal Kinase Promotes Dendrite Formation, Monika Podkowa, Xin Zhao, Chi-Wing Chow, Eleanor T. Coffey, Roger J. Davis, Liliana Attisano

Davis Lab Publications

Neuronal outgrowth occurs via coordinated remodeling of the cytoskeleton involving both actin and microtubules. Microtubule stabilization drives the extending neurite, yet little is known of the molecular mechanisms whereby extracellular cues regulate microtubule dynamics. Bone morphogenetic proteins (BMPs) play an important role in neuronal differentiation and morphogenesis, and BMP7 in particular induces the formation of dendrites. Here, we show that BMP7 induces stabilization of microtubules in both a MAP2-dependent neuronal cell culture model and in dendrites of primary cortical neurons. BMP7 rapidly activates c-Jun N-terminal kinases (JNKs), known regulators of microtubule dynamics, and we show that JNKs associate with the ...


Analysis Of Apoptosis Of Memory T Cells And Dendritic Cells During The Early Stages Of Viral Infection Or Exposure To Toll-Like Receptor Agonists, Kapil Bahl, Anette Hubner, Roger J. Davis, Raymond M. Welsh May 2010

Analysis Of Apoptosis Of Memory T Cells And Dendritic Cells During The Early Stages Of Viral Infection Or Exposure To Toll-Like Receptor Agonists, Kapil Bahl, Anette Hubner, Roger J. Davis, Raymond M. Welsh

Davis Lab Publications

Profound type I interferon (IFN-I)-dependent attrition of memory CD8 and CD4 T cells occurs early during many infections. It is dramatic at 2 to 4 days following lymphocytic choriomeningitis virus (LCMV) infection of mice and can be elicited by the IFN-inducing Toll receptor agonist poly(I:C). We show that this attrition occurs in many organs, indicating that it is due to T cell loss rather than redistribution. This loss correlated with elevated intracellular staining of T cells ex vivo for activated caspases but with only low levels of ex vivo staining with annexin V, probably due to the ...


C-Jun Nh2-Terminal Kinase Is Required For Lineage-Specific Differentiation But Not Stem Cell Self-Renewal, Ping Xu, Roger J. Davis Mar 2010

C-Jun Nh2-Terminal Kinase Is Required For Lineage-Specific Differentiation But Not Stem Cell Self-Renewal, Ping Xu, Roger J. Davis

Davis Lab Publications

The c-Jun NH(2)-terminal kinase (JNK) is implicated in proliferation. Mice with a deficiency of either the Jnk1 or the Jnk2 genes are viable, but a compound deficiency of both Jnk1 and Jnk2 causes early embryonic lethality. Studies using conditional gene ablation and chemical genetic approaches demonstrate that the combined loss of JNK1 and JNK2 protein kinase function results in rapid senescence. To test whether this role of JNK was required for stem cell proliferation, we isolated embryonic stem (ES) cells from wild-type and JNK-deficient mice. We found that Jnk1(-/-) Jnk2(-/-) ES cells underwent self-renewal, but these cells proliferated ...


Role Of The Hypothalamic-Pituitary-Thyroid Axis In Metabolic Regulation By Jnk1, Guadalupe Sabio, Julie Cavanagh-Kyros, Tamera Barrett, Dae Young Jung, Hwi Jin Ko, Helena Ong, Caroline Morel, Alfonso Mora, Judith Reilly, Jason K. Kim, Roger J. Davis Feb 2010

Role Of The Hypothalamic-Pituitary-Thyroid Axis In Metabolic Regulation By Jnk1, Guadalupe Sabio, Julie Cavanagh-Kyros, Tamera Barrett, Dae Young Jung, Hwi Jin Ko, Helena Ong, Caroline Morel, Alfonso Mora, Judith Reilly, Jason K. Kim, Roger J. Davis

Davis Lab Publications

The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic-pituitary-thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic-pituitary-thyroid axis represents an important target of metabolic signaling by JNK1.