Denise Cook - Academia.edu (original) (raw)
Uploads
Papers by Denise Cook
PLOS One, 2011
The formation and storage of memories in neuronal networks relies on new protein synthesis, which... more The formation and storage of memories in neuronal networks relies on new protein synthesis, which can occur locally at synapses using translational machinery present in dendrites and at spines. These new proteins support long-lasting changes in synapse strength and size in response to high levels of synaptic activity. To ensure that proteins are made at the appropriate time and location to enable these synaptic changes, messenger RNA (mRNA) translation is tightly controlled by dendritic RNA-binding proteins. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein with high homology to Fragile X Mental Retardation Protein (FMRP) and is known to repress and activate mRNA translation in non-neuronal cells. However, unlike FMRP, very little is known about the role of FXR1P in the central nervous system. To understand if FXR1P is positioned to regulate local mRNA translation in dendrites and at synapses, we investigated the expression and targeting of FXR1P in developing hippocampal neurons in vivo and in vitro. We found that FXR1P was highly expressed during hippocampal development and co-localized with ribosomes and mRNAs in the dendrite and at a subset of spines in mouse hippocampal neurons. Our data indicate that FXR1P is properly positioned to control local protein synthesis in the dendrite and at synapses in the central nervous system.
Human carcinoembryonic antigen (CEA), a widely used clinical tumor marker, and its close relative... more Human carcinoembryonic antigen (CEA), a widely used clinical tumor marker, and its close relative, CEACAM6, are often overexpressed in many cancers. This correlation suggests a possible instrumental role in tumorigenesis, which is supported by extensive results obtained with several in vitro systems. The implication that these results could also apply in vivo warrants investigation. Since mice do not possess homologs of the glycophosphatidyl inositol (GPI)-anchored CEACAM family genes CEA, CEACAM6 and CEACAM7, we have constructed transgenic mice harboring a 187 kb portion of the human CEACAM family gene locus contained in a bacterial artificial chromosome (CEABAC) that includes genes coding for CEA, CEACAM6 and CEACAM7. In this study, we treated the CEABAC mice and their wild-type littermates with azoxymethane (AOM) in order to induce colon tumor formation. At 20 weeks post-treatment, the CEABAC transgenics showed more than a 2-fold increase in mean tumor load relative to their wild-type littermates. Cell surface expression of CEA and CEACAM6 increased by 2-and 20-fold, respectively, in colonocytes from the tumors relative to colonocytes from non-AOM treated transgenics and a de-regulated spatial pattern of CEA/CEACAM6 expression was found in 'normal' crypts adjacent to the tumors, thus mimicking closely the situation in human colon tumorigenesis. A modestly increased incidence of b-catenin mutations also observed in the AOM-induced CEABAC tumors. These results show that expression of the human GPI-anchored CEACAM family genes predisposes mice to acquire and/or retain essential mutations necessary for sporadic colon tumor development.
PLOS One, 2011
The formation and storage of memories in neuronal networks relies on new protein synthesis, which... more The formation and storage of memories in neuronal networks relies on new protein synthesis, which can occur locally at synapses using translational machinery present in dendrites and at spines. These new proteins support long-lasting changes in synapse strength and size in response to high levels of synaptic activity. To ensure that proteins are made at the appropriate time and location to enable these synaptic changes, messenger RNA (mRNA) translation is tightly controlled by dendritic RNA-binding proteins. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein with high homology to Fragile X Mental Retardation Protein (FMRP) and is known to repress and activate mRNA translation in non-neuronal cells. However, unlike FMRP, very little is known about the role of FXR1P in the central nervous system. To understand if FXR1P is positioned to regulate local mRNA translation in dendrites and at synapses, we investigated the expression and targeting of FXR1P in developing hippocampal neurons in vivo and in vitro. We found that FXR1P was highly expressed during hippocampal development and co-localized with ribosomes and mRNAs in the dendrite and at a subset of spines in mouse hippocampal neurons. Our data indicate that FXR1P is properly positioned to control local protein synthesis in the dendrite and at synapses in the central nervous system.
Human carcinoembryonic antigen (CEA), a widely used clinical tumor marker, and its close relative... more Human carcinoembryonic antigen (CEA), a widely used clinical tumor marker, and its close relative, CEACAM6, are often overexpressed in many cancers. This correlation suggests a possible instrumental role in tumorigenesis, which is supported by extensive results obtained with several in vitro systems. The implication that these results could also apply in vivo warrants investigation. Since mice do not possess homologs of the glycophosphatidyl inositol (GPI)-anchored CEACAM family genes CEA, CEACAM6 and CEACAM7, we have constructed transgenic mice harboring a 187 kb portion of the human CEACAM family gene locus contained in a bacterial artificial chromosome (CEABAC) that includes genes coding for CEA, CEACAM6 and CEACAM7. In this study, we treated the CEABAC mice and their wild-type littermates with azoxymethane (AOM) in order to induce colon tumor formation. At 20 weeks post-treatment, the CEABAC transgenics showed more than a 2-fold increase in mean tumor load relative to their wild-type littermates. Cell surface expression of CEA and CEACAM6 increased by 2-and 20-fold, respectively, in colonocytes from the tumors relative to colonocytes from non-AOM treated transgenics and a de-regulated spatial pattern of CEA/CEACAM6 expression was found in 'normal' crypts adjacent to the tumors, thus mimicking closely the situation in human colon tumorigenesis. A modestly increased incidence of b-catenin mutations also observed in the AOM-induced CEABAC tumors. These results show that expression of the human GPI-anchored CEACAM family genes predisposes mice to acquire and/or retain essential mutations necessary for sporadic colon tumor development.