The Experts below are selected from a list of 33663 Experts worldwide ranked by ideXlab platform

Eric R. Kandel - One of the best experts on this subject based on the ideXlab platform.

  • integration of long term memory related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure
    Cell, 2002
    Co-Authors: Zhonghui Guan, Eric R. Kandel, Maurizio Giustetto, Stavros Lomvardas, Jounghun Kim, Maria Concetta Miniaci, James H Schwartz, Dimitris Thanos
    Abstract:

    Excitatory and inhibitory inputs converge on single neurons and are integrated into a coherent output. Although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In Aplysia, we find that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates. Chromatin immunoprecipitation assays show that 5-HT induces the downstream gene C/EBP by activating CREB1, which recruits CBP for histone acetylation, whereas FMRFa leads to CREB1 displacement by CREB2 and recruitment of HDAC5 to deacetylate histones. When the two transmitters are applied together, facilitation is blocked because CREB2 and HDAC5 displace CREB1-CBP, thereby deacetylating histones.

  • enhancement of memory related long term facilitation by apaf a novel transcription factor that acts downstream from both CREB1 and creb2
    Cell, 2000
    Co-Authors: Dusan Bartsch, Andrea Casadio, Kevin A. Karl, Maurizio Giustetto, Mirella Ghirardi, Huixiang Zhu, Eric R. Kandel
    Abstract:

    The memory for sensitization of the gill withdrawal reflex in Aplysia is reflected in facilitation of the monosynaptic connection between the sensory and motor neurons of the reflex. The switch from short- to long-term facilitation requires activation of CREB1, derepression of ApCREB2, and induction of ApC/EBP. In search for genes that act downstream from CREB1, we have identified a transcription activator, ApAF, which is stimulated by protein kinase A and can dimerize with both ApC/EBP and ApCREB2. ApAF is necessary for long-term facilitation induced by five pulses of serotonin, by activation of CREB1, or by derepression of ApCREB2. Overexpression of ApAF enhances the long-term facilitation further. Thus, ApAF is a candidate memory enhancer gene downstream from both CREB1 and ApCREB2.

  • CREB1 Encodes a Nuclear Activator, a Repressor, and a Cytoplasmic Modulator that Form a Regulatory Unit Critical for Long-Term Facilitation
    Cell, 1998
    Co-Authors: Dusan Bartsch, Andrea Casadio, Kevin A. Karl, Paulo Serodio, Eric R. Kandel
    Abstract:

    Abstract Although CREB seems to be important for memory formation, it is not known which of the isoforms of CREB, CREM, or ATF1 are expressed in the neurons that undergo long-term synaptic changes and what roles they have in memory formation. We have found a single Aplysia CREB1 gene homologous to both mammalian CREB and CREM and have characterized in the sensory neurons that mediate gill-withdrawal reflex the expression and function of the three proteins that it encodes: CREB1a, CREB1b, and CREB1c. CREB1a is a transcriptional activator that is both necessary and, upon phosphorylation, sufficient for long-term facilitation. CREB1b is a repressor of long-term facilitation. Cytoplasmic CREB1c modulates both the short- and long-term facilitation. Thus, in the sensory neurons, CREB1 encodes a critical regulatory unit converting short- to long-term synaptic changes.

Cindy K. Miranti - One of the best experts on this subject based on the ideXlab platform.

  • Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation
    Oncogene, 2021
    Co-Authors: M. J. Watson, Penny L. Berger, Sander B. Frank, Galen Hostetter, K. Banerjee, L. Tang, S. S. Ganguly, M. Winn, Cindy K. Miranti
    Abstract:

    The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.

  • Aberrant CREB1 Activation in Prostate Cancer Disrupts Normal Prostate Luminal Cell Differentiation
    'Springer Science and Business Media LLC', 2021
    Co-Authors: M. J. Watson, S. S. Ganguly, Pl Berger, Banerjee K, Sb Frank, Tang L, Hostetter G, Winn M, Cindy K. Miranti
    Abstract:

    The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.Department of Defense, W81XWH-14-1-0479 and W81XWH-17-1-0570 NIH/NCI P30 CA0230746 month embargo; published: 12 April 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu

Philip W Kantoff - One of the best experts on this subject based on the ideXlab platform.

  • abiraterone acetate induces CREB1 phosphorylation and enhances the function of the cbp p300 complex leading to resistance in prostate cancer cells
    Clinical Cancer Research, 2021
    Co-Authors: Wenting Pan, Zhouwei Zhang, Hannah Kimball, Kyler Berlind, Konrad H Stopsack, Gwoshu Mary Lee, Toni K Choueiri, Philip W Kantoff
    Abstract:

    Purpose: Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. Experimental Design: We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA-seq and phospho-kinase array screenings were performed to discover that the cAMP response element-CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development. Results: The drug-resistant cell lines are phenotypically stable without drug selections, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation re-sensitized AA-resistant cells to AA. AA treatment increases intracellular cAMP levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells, since AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetic studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. Conclusions: Our studies suggest that AA treatment upregulates pCREB1 which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.

  • abiraterone acetate induces CREB1 phosphorylation and enhances the function of the cbp p300 complex leading to resistance in prostate cancer cells
    Clinical Cancer Research, 2021
    Co-Authors: Wenting Pan, Zhouwei Zhang, Hannah Kimball, Kyler Berlind, Konrad H Stopsack, Gwoshu Mary Lee, Toni K Choueiri, Philip W Kantoff
    Abstract:

    Purpose: Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. Experimental Design: We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development. Results: The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. Conclusions: Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.

John H Byrne - One of the best experts on this subject based on the ideXlab platform.

  • the requirement for enhanced CREB1 expression in consolidation of long term synaptic facilitation and long term excitability in sensory neurons of aplysia
    The Journal of Neuroscience, 2011
    Co-Authors: Rong Yu Liu, Leonard J Cleary, John H Byrne
    Abstract:

    Accumulating evidence suggests that the transcriptional activator cAMP response element-binding protein 1 (CREB1) is important for serotonin (5-HT)-induced long-term facilitation (LTF) of the sensorimotor synapse in Aplysia. Moreover, CREB1 is among the genes activated by CREB1, suggesting a role for this protein beyond the induction phase of LTF. The time course of the requirement for CREB1 synthesis in the consolidation of long-term facilitation was examined using RNA interference techniques in sensorimotor cocultures. Injection of CREB1 small-interfering RNA (siRNA) immediately or 10 h after 5-HT treatment blocked LTF when measured at 24 and 48 h after treatment. In contrast, CREB1 siRNA did not block LTF when injected 16 h after 5-HT treatment. These results demonstrate that CREB1 expression must be sustained for a relatively long time to support the consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of sensory neurons (SNs). Because LTE was observed in the isolated SN after 5-HT treatment, this long-term change was intrinsic to that element of the circuit. LTE was blocked when CREB1 siRNA was injected into isolated SNs immediately after 5-HT treatment. These data suggest that 5-HT-induced CREB1 synthesis is required for consolidation of both LTF and LTE.

  • camp response element binding protein 1 feedback loop is necessary for consolidation of long term synaptic facilitation in aplysia
    The Journal of Neuroscience, 2008
    Co-Authors: Rong Yu Liu, Diasinou Fioravante, Shreyansh Shah, John H Byrne
    Abstract:

    The transcription factor cAMP response element (CRE)-binding protein (CREB) plays an essential role in the induction of many forms of long-term synaptic plasticity. Levels of CREB1, the Aplysia homolog of CREB, show sustained elevations for several hours after the induction of long-term synaptic facilitation (LTF). Furthermore, CREB1 binds to the promoter of its own gene. These results suggest the existence of a CREB1-positive feedback loop that contributes to the consolidation of LTF. In the present study, we provide a detailed, quantitative characterization of the dynamics of CREB1 mRNA and protein as well as CREB1 phosphorylation after LTF induction. Injections of CRE oligonucleotides prevented the increase in CREB1 in response to 5-HT, corroborating the existence of the CREB1 feedback loop. This loop probably sustains CRE-dependent gene transcription, which remains elevated for at least 12 h after LTF induction. LTF is blocked by injection of CREB1 antibody after the induction phase, suggesting that the CREB1-positive feedback is required for consolidation of LTF.

  • camp response elements in aplysia CREB1 creb2 and ap uch promoters implications for feedback loops modulating long term memory
    Journal of Biological Chemistry, 2005
    Co-Authors: Habib A Mohamed, Diasinou Fioravante, Weizhe Yao, Paul Smolen, John H Byrne
    Abstract:

    The Aplysia genes encoding for cAMP-response element-binding protein 1 (CREB1), CREB2, and ubiquitin C-terminal hydrolase (Ap-uch) have been implicated in the formation of long term memory. However, nothing is known about the promoter regions of these genes or the transcription factors that regulate them. We cloned the promoter regions of CREB1, creb2, and Ap-uch and identified a canonical cAMP-response element (CRE) in the promoter region of CREB1. Variants of the canonical CRE were identified in all three promoters. TATA boxes and C/EBP-binding motifs are also present in the promoter regions of these genes. Promoter immunoprecipitation assays and chromatin immunoprecipitation assays indicated that CREB1 and CREB2 bind to the promoter regions of CREB1 and creb2, suggesting that feedback loops modulate the formation of long term memory. In a positive feedback loop, phosphorylated CREB1 might induce its own gene via CREs. In support of this suggestion, treatment with serotonin enhanced binding of CREB1 to its promoter region and increased mRNA levels of CREB1. Levels of Ap-uch mRNA also increased in response to serotonin; however, binding of CREB1 or CREB2 to the promoter region of Ap-uch was not detected. The finding that the promoter region of creb2 has a CRE raises the intriguing possibility that its expression is regulated by CREB1 and/or CREB2. CREB2 may repress its own gene, forming a negative feedback loop, and CREB2 up-regulation via CREB1 may limit the activity of the CREB1-mediated positive feedback loop.

Marc Ladanyi - One of the best experts on this subject based on the ideXlab platform.

  • ewsr1 CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma
    Genes Chromosomes and Cancer, 2007
    Co-Authors: Cristina R Antonescu, Paola Dal Cin, Khedoudja Nafa, Lisa A Teot, Urvashi Surti, Christopher D M Fletcher, Marc Ladanyi
    Abstract:

    The molecular hallmark of angiomatoid fibrous histiocytoma (AFH) is not well defined, with only six cases with specific gene fusions reported to date, consisting of either FUS-ATF1 or EWSR1-ATF1. To address this, we investigated the presence of FUS-ATF1, EWSR1-ATF1, and the highly related EWSR1-CREB1 fusion in a group of nine AFHs. All cases were subjected to RT-PCR for EWSR1-ATF1 and EWSR1-CREB1. FISH for EWSR1 and FUS rearrangements was performed in most cases. Transcriptional profiling was performed in three tumors and their gene expression was compared to five clear cell sarcomas expressing either the EWSR1-ATF1 or EWSR1-CREB1 fusion. By RT-PCR, eight out of nine tumors showed the presence of the EWSR1-CREB1 fusion, while one had an EWSR1-ATF1 transcript. FISH showed evidence of EWSR1 rearrangement in seven out of eight cases. Karyotypic analysis performed in one tumor showed a t(2;22)(q33;q12). High transcript levels were noted for TFE3 in AFH tumors, while overexpression of genes involved in melanogenesis, such as MITF, GP100, and MET was noted in somatic clear cell sarcomas. We report for the first time the presence of EWSR1-CREB1 in AFH, which now appears to be the most frequent gene fusion in this tumor. EWSR1-CREB1 is a novel translocation recently described in clear cell sarcoma of the GI tract. EWSR1-ATF1, identified in some AFH cases, is the most common genetic abnormality in soft tissue clear cell sarcoma. Thus, identical fusions involving ATF1 and CREB1 are found in two distinct sarcomas, which may be able to transform two different types of mesenchymal precursor cells, unlike most other sarcoma gene fusions.

  • ewsr1 CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma
    Genes Chromosomes and Cancer, 2007
    Co-Authors: Cristina R Antonescu, Khedoudja Nafa, Lisa A Teot, Urvashi Surti, Christopher D M Fletcher, Marc Ladanyi
    Abstract:

    The molecular hallmark of angiomatoid fibrous histiocytoma (AFH) is not well defined, with only six cases with specific gene fusions reported to date, consisting of either FUS-ATF1 or EWSR1-ATF1. To address this, we investigated the presence of FUS-ATF1, EWSR1-ATF1, and the highly related EWSR1-CREB1 fusion in a group of nine AFHs. All cases were subjected to RT-PCR for EWSR1-ATF1 and EWSR1-CREB1. FISH for EWSR1 and FUS rearrangements was performed in most cases. Transcriptional profiling was performed in three tumors and their gene expression was compared to five clear cell sarcomas expressing either the EWSR1-ATF1 or EWSR1-CREB1 fusion. By RT-PCR, eight out of nine tumors showed the presence of the EWSR1-CREB1 fusion, while one had an EWSR1-ATF1 transcript. FISH showed evidence of EWSR1 rearrangement in seven out of eight cases. Karyotypic analysis performed in one tumor showed a t(2;22)(q33;q12). High transcript levels were noted for TFE3 in AFH tumors, while overexpression of genes involved in melanogenesis, such as MITF, GP100, and MET was noted in somatic clear cell sarcomas. We report for the first time the presence of EWSR1-CREB1 in AFH, which now appears to be the most frequent gene fusion in this tumor. EWSR1-CREB1 is a novel translocation recently described in clear cell sarcoma of the GI tract. EWSR1-ATF1, identified in some AFH cases, is the most common genetic abnormality in soft tissue clear cell sarcoma. Thus, identical fusions involving ATF1 and CREB1 are found in two distinct sarcomas, which may be able to transform two different types of mesenchymal precursor cells, unlike most other sarcoma gene fusions. © 2007 Wiley-Liss, Inc.