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TRANSCRIPTIONAL REGULATION BY THE RETINOBLASTOMA TUMOR SUPPRESSOR: NOVEL TARGETS AND MECHANISMSMARKEY, MICHAEL PATRICK 07 October 2004 (has links)
No description available.
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Multiple biological activities of the human papillomavirus type 16 E7 oncoprotein contribute to the abrogation of human epithelial cell cycle control /Helt, Anna-Marija. January 2002 (has links)
Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 111-140).
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The identification and characterisation of a novel Apoptotic Gene,Snama, in drosophila melanogasterMather, Arshad Saleh 15 November 2006 (has links)
Student Number : 9105022E -
PhD thesis -
School of Molecular and Cell Biology -
Faculty of Science / SNAMA is the Drosophila melanogaster homologue of a group of proteins that are
known to bind p53 and the retinoblastoma protein (Rb). This multi domain protein
consists of a conserved N-terminal domain called Domain With No Name (DWNN),
a zinc finger, a cysteine rich RING finger-like domain, a probable p53 binding
region, and a glutamic acid-rich and lysine-rich region. These associated domains
indicate that SNAMA plays an important regulatory role in the cell and may function
in RNA processing and in apoptosis.
The DWNN domain was first identified in Cytotoxic T-cell resistant Chinese hamster
ovary (CHO) cells using promoter trap mutagenesis to screen for genes involved in
apoptosis. Subsequently, this domain was identified in other eukaryotic organisms
including animals and plants.
The SNAMA transcriptional unit consists of 9 exons and 8 introns that code for a
1231 amino acid protein with the 76 residue N-terminal DWNN domain. The DWNN
domain has a 23.5% sequence identity to the ubiquitin protein and a predicted folded
structure similar to ubiquitin. Western blots identified multiple bands indicative of
ubiquitin tagged proteins. Taken together this suggests a role in the ubiquitin pathway
either as an ubiquitin domain protein or the DWNN domain of SNAMA tagging other
proteins. The cysteine rich RING finger-like domain has a histidine to serine
substitution at the fourth position of the putative RING finger and represents a distinct class of RING finger-like proteins that could have ubiquitin ligase activity.
Northern blot analysis identified a single 4.6 kbp transcript expressed abundantly
throughout development early in embryogenesis but reduced in older embryos and in
adult male and females. SNAMA probably interacts with Dmp53 as a suppressor of
apoptosis or a negative regulator of an activator of apoptosis. It is a vital gene
required for development, as the mutant P-element insertion line in which the Pelement
is inserted in the first intron of SNAMA is lethal when homozygous.
Acridine orange staining of these mutant flies showed a direct correlation between the
presence of SNAMA and apoptosis. An increase in the levels of apoptosis occurred in
embryos with relatively low levels of SNAMA expression. The mode of this action is
either direct, or via other proteins that are involved in the apoptotic pathway.
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Estudo do metabolismo de angiotensinas e mecanismos de sinalização intracelular modulados pela angiotensina (1-7) no sistema nervoso centralPEREIRA, Giorgia Lemes 30 August 2017 (has links)
Mais estudos sobre ações neuromoduladoras das angiotensinas no Sistema Renina
Angiotensina (SRA) poderiam melhorar a compreensão de muitas funções e
distúrbios do sistema nervoso central. A via de sinalização de
PTEN/PI3K/AKT/mTOR que pode ser ativada pela Angiotensina-(1-7) desempenha
um papel essencial na regulação do crescimento, metabolismo e sobrevivência das
células. Este estudo teve como objetivo identificar e descrever a(s) via(s)
metabólica(s) angiotensinérgica(s) principal(is) no hipocampo de camundongos (Mus
musculus); Estudar a regulação da cascata de sinalização PTEN/PI3K/Akt/mTOR a
partir da ativação com a Ang-(1-7) e realizar ensaios de inibição com o antagonista
do receptor Mas. Analisamos também a expressão das enzimas chave da cascata
de mTOR, com foco na enzima PTEN. Inicialmente foi realizada a identificação da
via metabólica angiotensinérgica no hipocampo de camundongos através do estudo
da atividade proteolítica angiotensinérgica com o extrato hipocampal de
camundongos Swiss para identificar as enzimas e peptídeos formados a partir de
AngI e/ou inibidores em HPLC. Para o estudo da regulação da cascata de
sinalização PTEN/PI3K/Akt/mTOR a partir da ativação/inibição do SRA os
experimentos foram realizados em células imortalizadas de neuroblastoma
denominadas SH-SY5Y e western blotting para determinação dos níveis de PTEN e
S6k (total e fosforilada). Nossos resultados mostraram que a caracterização do perfil
do sistema angiotensinérgico hipocampal gerou resultados preliminares, em que a
partir de AngI, o principal peptídeo formado foi a Ang-(1-7) e, em menor quantidade,
a Ang II. Concluímos então que a AngII pode estar sendo formada por
carboxipeptidades de forma geral e a Ang-(1-7) pode estar sendo formada por
endopeptidases. Além disso, a Ang-(1-7) provoca a diminuição da expressão da
PTEN total, bem como, a diminuição da fosforilação da PTEN, e nesse caso, a
diminuição da fosforilação significa geração de mais proteína desfosforilada e
aumento da atividade fosfatase resultando em efeitos neuroprotetores. Esses
resultados nos permitiram observar que em células SH-S5SY, o mecanismo pelo
qual a Ang-(1-7) ativa mecanismos neuroprotetores pode estar relacionado com a
ativação da enzima PTEN. / Further studies on neuromodulatory actions of angiotensins in the Renin Angiotensin
System (RAS) could improve understanding of many central nervous system
functions and disorders. The PTEN/PI3K/AKT/mTOR signaling pathway that can be
activated by Angiotensin-(1-7) plays an essential role in regulating cell growth,
metabolism and survival. The aim of this study was to identify and describe the main
angiotensinergic metabolic pathway(s) in the hippocampus of mice (Mus musculus);
Study the regulation of the PTEN/PI3K/Akt/mTOR signaling cascade from activation
with Ang-(1-7) and perform inhibition assays with the Mas receptor antagonist. We
also analyzed the expression of the key enzymes of the mTOR cascade, focusing on
the enzyme PTEN. Identification was initially performed of the angiotensinergic
metabolic pathway in the mouse hippocampus was performed by studying the
angiotensinergic proteolytic activity with the hippocampal extract of Swiss mice to
identify the enzymes and peptides formed from AngI and/or inhibitors in HPLC. For
the study of PTEN/PI3K/Akt/mTOR signaling cascade regulation from the
activation/inhibition of RAS the experiments were performed on immortalized
neuroblastoma cells called SH-SY5Y and western blotting for determination of PTEN
and S6k levels (total and phosphorylated). Our results showed that the
characterization of the profile of the hippocampal angiotensinergic system generated
preliminary results, in which from AngI, the main peptide formed was Ang-(1-7) and,
to a lesser extent, Ang II. We conclude that AngII may be formed by carboxypeptids
in general and Ang-(1-7) may be formed by endopeptidases. In addition, Ang-(1-7)
causes a decrease in total PTEN expression, as well as a decrease in PTEN
phosphorylation, in which case the decrease in phosphorylation means generation of
more dephosphorylated protein and increased phosphatase activity resulting In
neuroprotective effects. These results allowed us to observe that in SH-S5SY cells,
the mechanism by which Ang-(1-7) activates neuroprotective mechanisms may be
related to the activation of the PTEN enzyme. / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
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The Role of the Retinoblastoma Protein in Dentate Gyrus DevelopmentClark, Alysen 28 January 2013 (has links)
New neurons continue to be added to the dentate gyrus (DG) throughout adulthood and enhancing neurogenesis in this region holds therapeutic potential. However, the molecular mechanisms underlying DG neurogenesis remain elusive. Since developmental and adult neurogenesis often share the same signaling pathways, understanding how the DG develops is crucial to understanding adult neurogenesis. This study aims to determine the role of the retinoblastoma (Rb) protein in DG development and to determine if modulation of this pathway holds potential for enhancing neurogenesis in an adult system. A FoxG1 driven Cre is used to delete Rb in the developing forebrain and the resulting effects are analyzed in in vitro and in vivo mouse models. We show that Rb deletion enhances DG neurogenesis by specifically increasing proliferation of immature neurons. Overall this study suggests that Rb pathway modulation could hold potential for enhancing neurogenesis in the adult.
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Coordinating Cell Cycle Exit and Differentiation in the Mammalian Retina and its Dependence on RbPacal, Marek 06 December 2012 (has links)
Cell cycle exit (“birth”) of retinal progenitor cells (RPCs) is considered a watershed that is preceded by changing levels of cell cycle regulators, and followed rapidly by induction of a post M-phase differentiation cascade. Yet the actual dynamics of these events are largely unclear, thus whether mitosis separates pre- and post- birth differentiation cascades is unproven. We characterized the regulation of many division and differentiation markers relative to each other and final mitosis. Unexpectedly, classic “cell cycle” markers were present well beyond exit (e.g. Ki67, Pcna), early embryonic RPCs expressed “differentiation” markers that later labeled post-mitotic neurons
exclusively (e.g. Brn3b, Tubb3, Ptf1a), and factors detected just after cell birth in the
embryo were induced well beyond M-phase post-natally (e.g. Nrl, Crx). Thus, the dynamics of birth-associated events shift dramatically during development, even to either side of mitosis. Instead of mitosis behaving as a cog that activates post-exit
differentation events we suggest that a common trigger induces both the exit and
differentiation programs in RPCs, precisely coordinating their startpoints, but that each
subsequent cascade unfolds independently. This model explains the convergence of birth
and differentiation but also their temporal maliability. This view fits with our
observation that in the absence of the Rb tumor suppressor, differentiation still initiates even without cell cycle exit. Finally, neoplastic transformation in the mouse retina requires loss of Rb and its relative p107, and emerging tumor features suggest an amacrine cell-of-origin. We studied Rb/p107 null clones, and noted two striking features. First, despite initial expansion of aberrantly dividing differentiating cells, apoptosis
pruned clones precisely to wild type sizes. “Cell competition” maintains tissue size by selecting fitter over weaker progenitors; our data provide a unique example of competition among differentiating cells. Second, despite normal numbers of amacrine cells per Rb/p107 null clone, more clones contained amacrine cells and fewer had bipolar cells. Both this effect and ectopic division were E2f1-dependent. Thus, the oncogenic initiation event in mouse retinoblastoma triggers a very early fate switch, even before neoplastic transformation, broadening the possibilities for the cell-of-origin of retinoblastoma, and arguing that even very early stage tumors cannot be used to define cancer origin.
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Coordinating Cell Cycle Exit and Differentiation in the Mammalian Retina and its Dependence on RbPacal, Marek 06 December 2012 (has links)
Cell cycle exit (“birth”) of retinal progenitor cells (RPCs) is considered a watershed that is preceded by changing levels of cell cycle regulators, and followed rapidly by induction of a post M-phase differentiation cascade. Yet the actual dynamics of these events are largely unclear, thus whether mitosis separates pre- and post- birth differentiation cascades is unproven. We characterized the regulation of many division and differentiation markers relative to each other and final mitosis. Unexpectedly, classic “cell cycle” markers were present well beyond exit (e.g. Ki67, Pcna), early embryonic RPCs expressed “differentiation” markers that later labeled post-mitotic neurons
exclusively (e.g. Brn3b, Tubb3, Ptf1a), and factors detected just after cell birth in the
embryo were induced well beyond M-phase post-natally (e.g. Nrl, Crx). Thus, the dynamics of birth-associated events shift dramatically during development, even to either side of mitosis. Instead of mitosis behaving as a cog that activates post-exit
differentation events we suggest that a common trigger induces both the exit and
differentiation programs in RPCs, precisely coordinating their startpoints, but that each
subsequent cascade unfolds independently. This model explains the convergence of birth
and differentiation but also their temporal maliability. This view fits with our
observation that in the absence of the Rb tumor suppressor, differentiation still initiates even without cell cycle exit. Finally, neoplastic transformation in the mouse retina requires loss of Rb and its relative p107, and emerging tumor features suggest an amacrine cell-of-origin. We studied Rb/p107 null clones, and noted two striking features. First, despite initial expansion of aberrantly dividing differentiating cells, apoptosis
pruned clones precisely to wild type sizes. “Cell competition” maintains tissue size by selecting fitter over weaker progenitors; our data provide a unique example of competition among differentiating cells. Second, despite normal numbers of amacrine cells per Rb/p107 null clone, more clones contained amacrine cells and fewer had bipolar cells. Both this effect and ectopic division were E2f1-dependent. Thus, the oncogenic initiation event in mouse retinoblastoma triggers a very early fate switch, even before neoplastic transformation, broadening the possibilities for the cell-of-origin of retinoblastoma, and arguing that even very early stage tumors cannot be used to define cancer origin.
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PsRBR1 encodes a pea retinoblastoma-related protein that is phosphorylated in axillary buds during dormancy-to-growth transitionShimizu-Sato, Sae, Ike, Yoko, Mori, Hitoshi, 森, 仁志 01 1900 (has links)
Open Access Article
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The Role of the Retinoblastoma Protein in Dentate Gyrus DevelopmentClark, Alysen 28 January 2013 (has links)
New neurons continue to be added to the dentate gyrus (DG) throughout adulthood and enhancing neurogenesis in this region holds therapeutic potential. However, the molecular mechanisms underlying DG neurogenesis remain elusive. Since developmental and adult neurogenesis often share the same signaling pathways, understanding how the DG develops is crucial to understanding adult neurogenesis. This study aims to determine the role of the retinoblastoma (Rb) protein in DG development and to determine if modulation of this pathway holds potential for enhancing neurogenesis in an adult system. A FoxG1 driven Cre is used to delete Rb in the developing forebrain and the resulting effects are analyzed in in vitro and in vivo mouse models. We show that Rb deletion enhances DG neurogenesis by specifically increasing proliferation of immature neurons. Overall this study suggests that Rb pathway modulation could hold potential for enhancing neurogenesis in the adult.
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Expressão imunohistoquímica da proteína pRb na mucosa esofágica de indivíduos sob risco para carcinoma epidermóide de esôfagoContu, Simone Santana January 2001 (has links)
O câncer de esôfago é a sexta neoplasia maligna mais comum no mundo. No Rio Grande do Sul, Brasil, o carcinoma epidermóide de esôfago apresenta coeficientes de mortalidade elevados e com tendência ascendente com, pelo menos, o dobro dos coeficientes padronizados de mortalidade encontrados em outros estados brasileiros ou em países do cone sul da América latina. O diagnóstico tardio parece ser o principal responsável pelo mau prognóstico. Nos últimos anos, diversos estudos têm demonstrado a possibilidade de identificação das lesões precursoras do câncer esofágico, mas sem repercussão no prognóstico, até o momento. Considera-se, atualmente, que a carcinogênese esofágica está relacionada a uma interação entre fatores ambientais e anormalidades genéticas Recentemente, estudos em biologia molecular têm demonstrado a influência dos fatores reguladores do ciclo celular no prognóstico de diversas moléstias, inclusive o câncer. O Rb é um gene supressor tumoral envolvido no mecanismo de controle do ciclo celular, cuja expressão tem sido demonstrada no câncer do esôfago. O objetivo deste estudo foi determinar a prevalência da perda da expressão da proteína pRb na mucosa esofágica de indivíduos sob risco para o carcinoma epidermóide de esôfago, bem como relacionar esta expressão com o consumo de tabaco, álcool e chimarrão, achados histopatológicos e cromoscopia com lugol. Foram estudados 170 casos e 20 controles através de reação imunohistoquímica utilizando anticorpo monoclonal anti-pRb em amostras teciduais fixadas em formalina e armazenadas em parafina. Um total de 33 casos demonstrou perda da expressão imunohistoquímica da proteína pRb, determinando uma prevalência de 19,4% na amostra estudada. Não houve associação estatisticamente significativa entre a perda da expressão da proteína pRb e as variáveis idade, raça, exposição ao fumo, álcool e chimarrão, bem como a cromoendoscopia com lugol. Foi demonstrada uma associação significativa entre a perda da expressão da pRb com a história de câncer na família. Da mesma forma, foi demonstrada uma associação linear significativa entre a perda da pRb e o grau histopatológico das lesões. Estes resultados demonstraram uma influência da proteína pRb na evolução da carcinogênese esofágica e permitem sugerir que os indivíduos expostos aos fatores de risco estudados sejam candidatos a uma maior vigilância.
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