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1.
Cell ; 150(3): 563-74, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22863009

RESUMO

Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis.


Assuntos
Genes Supressores de Tumor , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tristetraprolina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estabilidade de RNA , RNA Mensageiro/química
2.
Adv Exp Med Biol ; 1430: 71-89, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37526843

RESUMO

Research and development of gene therapies and cell- or tissue-based therapies has experienced exponential growth in recent decades and the potential for these products to treat diverse, often rare, clinical indications is promising. The Office of Therapeutic Products (OTP) in the Center for Biologics Evaluation and Research (CBER) at the United States Food and Drug Administration (US FDA) is responsible for the regulation of these products, among others, throughout the entire product lifecycle. This chapter provides an overview of the science- and data-driven approach to US FDA regulatory oversight of cell and gene therapy (CGT) products to ensure their safety and efficacy.


Assuntos
Aprovação de Drogas , Terapia Genética , Humanos , Estados Unidos , United States Food and Drug Administration
3.
Proc Natl Acad Sci U S A ; 114(16): 4153-4158, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28377514

RESUMO

Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues. In functional studies, SMARCE1 promotes invasion of in situ cancers growing within primary human mammary tissues and is also required for metastasis in vivo. Mechanistically, SMARCE1 drives invasion by forming a SWI/SNF-independent complex with the transcription factor ILF3. In patients diagnosed with early-stage cancers, SMARCE1 expression is a strong predictor of eventual relapse and metastasis. Collectively, these findings establish SMARCE1 as a key driver of invasive progression in early-stage tumors.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Movimento Celular , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Recidiva Local de Neoplasia/patologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
PLoS Biol ; 12(9): e1001945, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25203443

RESUMO

Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy.


Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Experimentais/genética , Fator 2 Relacionado a NF-E2/genética , Recidiva Local de Neoplasia/genética , eIF-2 Quinase/genética , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Desdiferenciação Celular/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Fator 2 Relacionado a NF-E2/metabolismo , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Oxirredução , Fosforilação , Transdução de Sinais , Transcrição Gênica , eIF-2 Quinase/metabolismo
5.
PLoS Comput Biol ; 11(4): e1004161, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25894653

RESUMO

The search for genes that regulate stem cell self-renewal and differentiation has been hindered by a paucity of markers that uniquely label stem cells and early progenitors. To circumvent this difficulty we have developed a method that identifies cell-state regulators without requiring any markers of differentiation, termed Perturbation-Expression Analysis of Cell States (PEACS). We have applied this marker-free approach to screen for transcription factors that regulate mammary stem cell differentiation in a 3D model of tissue morphogenesis and identified RUNX1 as a stem cell regulator. Inhibition of RUNX1 expanded bipotent stem cells and blocked their differentiation into ductal and lobular tissue rudiments. Reactivation of RUNX1 allowed exit from the bipotent state and subsequent differentiation and mammary morphogenesis. Collectively, our findings show that RUNX1 is required for mammary stem cells to exit a bipotent state, and provide a new method for discovering cell-state regulators when markers are not available.


Assuntos
Diferenciação Celular/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Glândulas Mamárias Humanas/citologia , Células-Tronco/citologia , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Perfilação da Expressão Gênica , Humanos , Organoides/citologia , Organoides/metabolismo , Biologia de Sistemas
6.
Int J Cancer ; 132(3): E128-38, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22907529

RESUMO

The RNA-binding proteins TTP and HuR control expression of numerous genes associated with breast cancer pathogenesis by regulating mRNA stability. However, the role of genetic variation in TTP (ZFP36) and HuR (ELAVL1) genes is unknown in breast cancer prognosis. A total of 251 breast cancer patients (170 Caucasians and 81 African-Americans) were enrolled and followed up from 2001 to 2011 (or until death). Genotyping was performed for 10 SNPs in ZFP36 and 7 in ELAVL1 genes. On comparing both races with one another, significant differences were found for clinical and genetic variables. The influence of genetic polymorphisms on survival was analyzed by using Cox-regression, Kaplan-Meier analysis and the log-rank test. Univariate (Kaplan-Meier/Cox-regression) and multivariate (Cox-regression) analysis showed that the TTP gene polymorphism ZFP36*2 A > G was significantly associated with poor prognosis of Caucasian patients (HR = 2.03; 95% CI = 1.09-3.76; p = 0.025; log-rank p = 0.022). None of the haplotypes, but presence of more than six risk genotypes in Caucasian patients, was significantly associated with poor prognosis (HR=2.42; 95% CI = 1.17-4.99; p = 0.017; log-rank p = 0.007). The effect of ZFP36*2 A > G on gene expression was evaluated from patients' tissue samples. Both TTP mRNA and protein expression was significantly decreased in ZFP36*2 G allele carriers compared to A allele homozygotes. Conversely, upregulation of the TTP-target gene COX-2 was observed ZFP36*2 G allele carriers. Through its ability to attenuate TTP gene expression, the ZFP36*2 A > G gene polymorphism has appeared as a novel prognostic breast cancer marker in Caucasian patients.


Assuntos
Antígenos de Superfície/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Tristetraprolina/genética , Negro ou Afro-Americano/genética , Neoplasias da Mama/etnologia , Ciclo-Oxigenase 2/biossíntese , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Feminino , Variação Genética , Genótipo , Humanos , Estimativa de Kaplan-Meier , Prognóstico , RNA Mensageiro , Fatores de Risco , População Branca/genética
7.
Gastroenterology ; 136(5): 1669-79, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19208339

RESUMO

BACKGROUND & AIMS: During tumorigenesis, loss of rapid messenger RNA (mRNA) decay allows for overexpression of cancer-associated genes. The RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) bind AU-rich elements in the 3' untranslated region of many cancer-associated mRNAs and target them for stabilization or rapid decay, respectively. We examined the functions of HuR and TTP during colon tumorigenesis and their ability to regulate cyclooxygenase (COX-2), a mediator of prostaglandin synthesis that increases in the colon tumor microenvironment. METHODS: We evaluated expression of HuR and TTP during colorectal tumorigenesis and in colon cancer cells and associated them with COX-2 expression. HuR and TTP-inducible cells were created to investigate HuR- and TTP-mediated regulation of COX-2. RESULTS: In normal colon tissues, low levels of nuclear HuR and higher levels of TTP were observed. By contrast, increased HuR expression and cytoplasmic localization were observed in 76% of adenomas and 94% of adenocarcinomas, and TTP expression was lost in >75% of adenomas and adenocarcinomas. Similar results were obtained for HuR and TTP mRNA levels in normal and staged tumor samples. In both adenomas and adenocarcinomas, COX-2 overexpression was associated with increased HuR and decreased TTP (P < .0001); similar associations were observed in colon cancer cells. HuR overexpression in cells up-regulated COX-2 expression, whereas overexpression of TTP inhibited it; limited TTP expression antagonized HuR-mediated COX-2 overexpression. CONCLUSIONS: Increased expression of the mRNA stability factor HuR and loss of the decay factor TTP occurs during early stages of colorectal tumorigenesis. These changes promote COX-2 overexpression and could contribute to colon tumorigenesis.


Assuntos
Antígenos de Superfície/fisiologia , Neoplasias do Colo/metabolismo , Ciclo-Oxigenase 2/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a RNA/fisiologia , Tristetraprolina/fisiologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenoma/genética , Adenoma/metabolismo , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Ciclo-Oxigenase 2/metabolismo , Citoplasma/metabolismo , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Células HeLa , Humanos , Imuno-Histoquímica , RNA Mensageiro/análise , Proteínas de Ligação a RNA/metabolismo , Transfecção , Tristetraprolina/metabolismo
8.
Biomolecules ; 5(3): 2035-55, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26343742

RESUMO

The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors (Trichostatin A, SAHA and sodium butyrate) promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells) and cervix carcinoma cells (HeLa). We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1). Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer.


Assuntos
Neoplasias Colorretais/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Tristetraprolina/metabolismo , Ácido Butírico/farmacologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Epigênese Genética , Humanos , Ácidos Hidroxâmicos/farmacologia , RNA Mensageiro/metabolismo , Tristetraprolina/genética , Vorinostat
9.
Mol Cell Biol ; 34(2): 180-95, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24190969

RESUMO

Transforming growth factor ß (TGF-ß) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3' untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-ß inhibited ARE-mRNA expression. This effect of TGF-ß was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-ß/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-ß induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-ß-dependent P-body formation and promoted growth inhibition by TGF-ß. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-ß/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-ß's antiproliferative properties and identify TGF-ß as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.


Assuntos
RNA Mensageiro/genética , Ativação Transcricional , Fator de Crescimento Transformador beta/fisiologia , Tristetraprolina/metabolismo , Regiões 3' não Traduzidas , Elementos Ricos em Adenilato e Uridilato , Animais , Sítios de Ligação , Linhagem Celular , Proliferação de Células , Senescência Celular , Colo/citologia , Estruturas Citoplasmáticas/metabolismo , Mucosa Intestinal/citologia , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Processamento Pós-Transcricional do RNA , Estabilidade de RNA , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais , Proteína Smad3/metabolismo , Tristetraprolina/genética
10.
Cancer Discov ; 4(6): 702-15, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24705811

RESUMO

UNLABELLED: Epithelial-to-mesenchymal transition (EMT) promotes both tumor progression and drug resistance, yet few vulnerabilities of this state have been identified. Using selective small molecules as cellular probes, we show that induction of EMT greatly sensitizes cells to agents that perturb endoplasmic reticulum (ER) function. This sensitivity to ER perturbations is caused by the synthesis and secretion of large quantities of extracellular matrix (ECM) proteins by EMT cells. Consistent with their increased secretory output, EMT cells display a branched ER morphology and constitutively activate the PERK-eIF2α axis of the unfolded protein response (UPR). Protein kinase RNA-like ER kinase (PERK) activation is also required for EMT cells to invade and metastasize. In human tumor tissues, EMT gene expression correlates strongly with both ECM and PERK-eIF2α genes, but not with other branches of the UPR. Taken together, our findings identify a novel vulnerability of EMT cells, and demonstrate that the PERK branch of the UPR is required for their malignancy. SIGNIFICANCE: EMT drives tumor metastasis and drug resistance, highlighting the need for therapies that target this malignant subpopulation. Our findings identify a previously unrecognized vulnerability of cancer cells that have undergone an EMT: sensitivity to ER stress. We also find that PERK-eIF2α signaling, which is required to maintain ER homeostasis, is also indispensable for EMT cells to invade and metastasize.


Assuntos
Estresse do Retículo Endoplasmático/genética , Transição Epitelial-Mesenquimal/genética , Fator de Iniciação 2 em Eucariotos/genética , eIF-2 Quinase/genética , Fator 4 Ativador da Transcrição/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos SCID , Resposta a Proteínas não Dobradas , eIF-2 Quinase/metabolismo
11.
Front Biosci (Landmark Ed) ; 17(1): 174-88, 2012 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-22201737

RESUMO

Messenger RNA decay is a critical mechanism to control the expression of many inflammation- and cancer-associated genes. These transcripts are targeted for rapid degradation through AU-rich element (ARE) motifs present in the mRNA 3' untranslated region (3'UTR). Tristetraprolin (TTP) is an RNA-binding protein that plays a significant role in regulating the expression of ARE-containing mRNAs. Through its ability to bind AREs and target the bound mRNA for rapid degradation, TTP can limit the expression of a number of critical genes frequently overexpressed in inflammation and cancer. Regulation of TTP occurs on multiple levels through cellular signaling events to control transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TTP's ability to promote ARE-mediated mRNA decay along with decay-independent functions of TTP. This review summarizes the current understanding of post-transcriptional regulation of ARE-containing gene expression by TTP and discusses its role in maintaining homeostasis and the pathological consequences of losing TTP expression.


Assuntos
Inflamação/metabolismo , Neoplasias/metabolismo , Tristetraprolina/metabolismo , Animais , Feminino , Humanos , Inflamação/genética , Masculino , Camundongos , Modelos Biológicos , Neoplasias/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tristetraprolina/genética
12.
Wiley Interdiscip Rev RNA ; 2(1): 42-57, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21278925

RESUMO

Adenylate- and uridylate-rich element (ARE) motifs are cis-acting elements present in the 3' untranslated region of mRNA transcripts that encode many inflammation- and cancer-associated genes. The TIS11 family of RNA-binding proteins, composed of tristetraprolin (TTP) and butyrate response factors 1 and 2 (BRF-1 and -2), plays a critical role in regulating the expression of ARE-containing mRNAs. Through their ability to bind and target ARE-containing mRNAs for rapid degradation, this class of RNA-binding proteins serves a fundamental role in limiting the expression of a number of critical genes, thereby exerting anti-inflammatory and anti-cancer effects. Regulation of TIS11 family members occurs on a number of levels through cellular signaling events to control their transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TIS11 members' ability to promote ARE-mediated mRNA decay along with decay-independent functions. This review summarizes our current understanding of posttranscriptional regulation of ARE-containing gene expression by TIS11 family members and discusses their role in maintaining normal physiological processes and the pathological consequences in their absence.


Assuntos
Fator 1 de Resposta a Butirato/fisiologia , Estabilidade de RNA/genética , Fatores de Transcrição/fisiologia , Tristetraprolina/fisiologia , Animais , Fator 1 de Resposta a Butirato/genética , Fator 1 de Resposta a Butirato/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Modelos Biológicos , Neoplasias/genética , Neoplasias/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tristetraprolina/genética , Tristetraprolina/metabolismo
13.
Aging (Albany NY) ; 1(9): 803-17, 2009 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-20157568

RESUMO

The RNA-binding protein tristetraprolin (TTP) regulates expression of many cancer-associated and proinflammatory factors through binding AU-rich elements (ARE) in the 3'-untranslated region (3'UTR) and facilitating rapid mRNA decay. Here we report on the ability of TTP to act in an anti-proliferative capacity in HPV18-positive HeLa cells by inducing senescence. HeLa cells maintain a dormant p53 pathway and elevated telomerase activity resulting from HPV-mediated transformation, whereas TTP expression counteracted this effect by stabilizing p53 protein and inhibiting hTERT expression. Presence of TTP did not alter E6 and E7 viral mRNA levels indicating that these are not TTP targets. It was found that TTP promoted rapid mRNA decay of the cellular ubiquitin ligase E6-associated protein (E6-AP). RNA-binding studies demonstrated TTP and E6-AP mRNA interaction and deletion of the E6-AP mRNA ARE-containing 3'UTR imparts resistance to TTP-mediated downregulation. Similar results were obtained with high-risk HPV16-positive cells that employ the E6-AP pathway to control p53 and hTERT levels. Furthermore, loss of TTP expression was consistently observed in cervical cancer tissue compared to normal tissue. These findings demonstrate the ability of TTP to act as a tumor suppressor by inhibiting the E6-AP pathway and indicate TTP loss to be a critical event during HPV-mediated carcinogenesis.


Assuntos
Alphapapillomavirus , Senescência Celular/fisiologia , Tristetraprolina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias do Colo do Útero/metabolismo , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Colo do Útero/metabolismo , Proteínas de Ligação a DNA/genética , Epitélio/metabolismo , Feminino , Expressão Gênica/genética , Meia-Vida , Células HeLa , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Modelos Biológicos , Proteínas Oncogênicas Virais/genética , Ligação Proteica/genética , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Telomerase/genética , Telomerase/metabolismo , Transfecção , Tristetraprolina/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Neoplasias do Colo do Útero/virologia , beta-Galactosidase/metabolismo
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