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See detailFurther pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.
Van de Veire, Sara; Stalmans, Ingeborg; Heindryckx, Femke et al

in Cell (2010), 141(1), 178-90

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as ... [more ▼]

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies. [less ▲]

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See detailHuman TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.
Tischfield, Max A; Baris, Hagit N; Wu, Chen et al

in Cell (2010), 140(1), 74-87

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 ... [more ▼]

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals. [less ▲]

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See detailElongator controls the migration and differentiation of cortical neurons through acetylation of a tubulin
Creppe, Catherine ULg; Malinouskaya, Lina ULg; Volvert, Marie-Laure ULg et al

in Cell (2009), 136

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which ... [more ▼]

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha tubulin. A direct reduction of alpha tubulin acetylation leads to comparable defects in cortical neurons and suggests that alpha tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons. [less ▲]

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See detailOncogene-induced senescence relayed by an interleukin-dependent inflammatory network.
Kuilman, Thomas; Michaloglou, Chrysiis; Vredeveld, Liesbeth C. W. et al

in Cell (2008), 133(6), 1019-1031

Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using combined ... [more ▼]

Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using combined genetic and bioinformatic analysis, we find that OIS is linked specifically to the activation of an inflammatory transcriptome. Induced genes included the pleiotropic cytokine interleukin-6 (IL-6), which upon secretion by senescent cells acted mitogenically in a paracrine fashion. Unexpectedly, IL-6 was also required for the execution of OIS, but in a cell-autonomous mode. Its depletion caused the inflammatory network to collapse and abolished senescence entry and maintenance. Furthermore, we demonstrate that the transcription factor C/EBPbeta cooperates with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically colocalized with arrested, p16(INK4A)-positive epithelium. We propose a model in which the context-dependent cytostatic and promitogenic functions of specific interleukins contribute to connect senescence with an inflammatory phenotype and cancer. [less ▲]

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See detailA cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy
Hilfiker-Kleiner, D.; Kaminski, K.; Podewski, E. et al

in Cell (2007), 128(3), 589-600

Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 ... [more ▼]

Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitior of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM. [less ▲]

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See detailGalectins: a family of animal beta-galactoside-binding lectins.
Barondes, S. H.; Castronovo, Vincenzo ULg; Cooper, D. N. et al

in Cell (1994), 76(4), 597-8

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See detailThe oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers.
Bours, Vincent ULg; Franzoso, G.; Azarenko, V. et al

in Cell (1993), 72(5), 729-39

Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly ... [more ▼]

Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly with p50B (NFKB2, p52) homodimers in cells, and together these proteins form a ternary complex with DNA at kappa B sites. Such an association functionally leads to a novel and potent form of transactivation through the kappa B motif: the tethering of Bcl-3 to DNA via the p50B homodimers allows Bcl-3 to transactivate directly, while p50B homodimers alone cannot. Transactivation mediated by Bcl-3 requires two cooperating domains located amino- and carboxy-terminal to the ankyrin domain. Bcl-3 is localized to the nucleus, and a Bcl-3-p50B complex is detected in certain lymphoid cells. Our data reveal a novel role for Bcl-3, distinct from that of the inhibitor I kappa B. The results have implications for tumorigenesis. [less ▲]

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See detailNucleotide sequence of part of the gene for human chorionic somatomammotropin: purification of DNA complementary to predominant mRNA species
Seeburg, Peter H; Shine, John; Martial, Joseph ULg et al

in Cell (1977), 12(1), 157-65

A novel purification procedure for DNA complementary to individual mRNA species has been developed by using restriction endonuclease cleavage of cDNA transcribed from a complex mixture of mRNAs. This ... [more ▼]

A novel purification procedure for DNA complementary to individual mRNA species has been developed by using restriction endonuclease cleavage of cDNA transcribed from a complex mixture of mRNAs. This procedure has allowed us to isolate and analyze DNA fragments complementary to the mRNA coding for the human peptide hormone chorionic somatomammotropin (HCS). The mRNA for this hormone is a major constituent of placental polyadenylated RNA as shown by in vitro translation of placental RNA and by nucleic acid hybridization using HCS cDNA as a specific probe. The purification of HCS cDNA was achieved by Hae III and Hha I restriction endonuclease cleavage of single-stranded cDNA synthesized in vitro from total polyadenylated placental RNA. Polyacrylamide gel electrophoresis of the products allowed detection and purification of discrete DNA fragments. A comparison of the nucleotide sequence of these fragments with that predicted from the amino acid sequence of HCS demonstrated that the fragments are transcripts of HCS mRNA, containing most of the translated and 3′ untranslated regions. The latter region is characterized by a UAG termination codon immediately adjacent to the translated region (a second in phase UAG occurs 9 nucleotides away) and a palindromic sequence (GUGACCCCUCCCCAGUG) centered 27 nucleotides from the termination codon. The purification scheme outlined for HCS cCNA should be applicable to DNA sequences complementary to mRNA species which represent at least 2% of any polyadenylated RNA preparation. This was demonstrated by restriction endonuclease cleavage of cDNA synthesized from a mixture of purified rabbit globin and total polyadenylated human placental RNAs. [less ▲]

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