RESUMO
Marek's disease (MD) is a neoplastic disease that significantly affects the poultry industry. Long non-coding RNAs (lncRNAs) are crucial regulatory factors in various biological processes, including tumourigenesis. However, the involvement of novel lncRNAs in the course of MD virus (MDV) infection is still underexplored. Here, we present the first comprehensive characterization of differentially expressed lncRNAs in chicken spleen at different stages of MDV infection. A series of differentially expressed lncRNAs was identified at each stage of MDV infection through screening. Notably, our investigation revealed a novel lncRNA, lncRNA 803, which exhibited significant differential expression at different stages of MDV infection and was likely to be associated with the p53 pathway. Further analyses demonstrated that the overexpression of lncRNA 803 positively regulated the expression of p53 and TP53BP1 in DF-1 cells, leading to the inhibition of apoptosis. This is the first study to focus on the lncRNA expression profiles in chicken spleens during MDV pathogenesis. Our findings highlight the potential role of the p53-related novel lncRNA 803 in MD pathogenesis and provide valuable insights for decoding the molecular mechanism of MD pathogenesis involving non-coding RNA.RESEARCH HIGHLIGHTS Differentially expressed lncRNAs in spleens of chickens infected with Marek's disease virus at different stages were identified for the first time.The effects of novel lncRNA 803 on p53 pathway and apoptosis of DF-1 cells were reported for the first time.
Assuntos
Apoptose , Galinhas , Doença de Marek , Doenças das Aves Domésticas , RNA Longo não Codificante , Baço , Proteína Supressora de Tumor p53 , Animais , RNA Longo não Codificante/genética , Doença de Marek/virologia , Doença de Marek/genética , Galinhas/virologia , Baço/virologia , Baço/patologia , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Herpesvirus Galináceo 2/genética , Herpesvirus Galináceo 2/fisiologiaRESUMO
BACKGROUND: The environmental oxygen tension has been reported to impact the blastocyst quality and cell numbers in the inner cell mass (ICM) during human and murine embryogenesis. While the molecular mechanisms leading to increased ICM cell numbers and pluripotency gene expression under hypoxia have been deciphered, it remains unknown which regulatory pathways caused the underweight fetal body and overweight placenta after maternal exposure to hyperbaric oxygen (HBO). RESULTS: The blastocysts from the HBO-exposed pregnant mice revealed significantly increased signals of reactive oxygen species (ROS) and nuclear Nrf2 staining, decreased Nf2 and Oct4 expression, increased nuclear Tp53bp1 and active caspase-3 staining, and ectopic nuclear signals of Cdx2, Yap, and the Notch1 intracellular domain (N1ICD) in the ICM. In the ICM of the HBO-exposed blastocysts, both Nf2 cDNA microinjection and Nrf2 shRNA microinjection significantly decreased the ectopic nuclear expression of Cdx2, Tp53bp1, and Yap whereas increased Oct4 expression, while Nrf2 shRNA microinjection also significantly decreased Notch1 mRNA levels and nuclear expression of N1ICD and active caspase-3. CONCLUSION: We show for the first time that maternal exposure to HBO at the preimplantation stage induces apoptosis and impairs ICM cell specification via upregulating Nrf2-Notch1-Cdx2 expression and downregulating Nf2-Oct4 expression.
RESUMO
Replication timing (RT) is a cellular program to coordinate initiation of DNA replication in all origins within the genome. RIF1 (replication timing regulatory factor 1) is a master regulator of RT in human cells. This role of RIF1 is associated with binding G4-quadruplexes and changes in 3D chromatin that may suppress origin activation over a long distance. Many effects of RIF1 in fork reactivation and DNA double-strand (DSB) repair (DSBR) are underlined by its interaction with TP53BP1 (tumor protein p53 binding protein). In G1, RIF1 acts antagonistically to BRCA1 (BRCA1 DNA repair associated), suppressing end resection and homologous recombination repair (HRR) and promoting non-homologous end joining (NHEJ), contributing to DSBR pathway choice. RIF1 is an important element of intra-S-checkpoints to recover damaged replication fork with the involvement of HRR. High-resolution microscopic studies show that RIF1 cooperates with TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs. Apart from TP53BP1, RIF1 interact with many other proteins, including proteins involved in DNA damage response, cell cycle regulation, and chromatin remodeling. As impaired RT, DSBR and fork reactivation are associated with genomic instability, a hallmark of malignant transformation, RIF1 has a diagnostic, prognostic, and therapeutic potential in cancer. Further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by RIF1.
Assuntos
Reparo do DNA/fisiologia , Período de Replicação do DNA/fisiologia , Proteínas de Ligação a Telômeros/metabolismo , Proteína BRCA1/metabolismo , Cromatina/metabolismo , DNA/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/genética , Reparo do DNA por Junção de Extremidades/fisiologia , Replicação do DNA/genética , Replicação do DNA/fisiologia , Período de Replicação do DNA/genética , Instabilidade Genômica/genética , Humanos , Reparo de DNA por Recombinação , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/fisiologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismoRESUMO
Meiotic oocytes lack classic centrosomes; therefore, bipolar spindle assembly depends on the clustering of acentriolar microtubule-organizing centers (MTOCs) into two poles. The bipolar spindle is an essential cellular component that ensures accurate chromosome segregation during anaphase. If the spindle does not form properly, it can result in aneuploidy or cell death. However, the molecular mechanism by which the bipolar spindle is established is not yet fully understood. Tumor suppressor p53-binding protein 1 (TP53BP1) is known to mediate the DNA damage response. Several recent studies have indicated that TP53BP1 has noncanonical roles in processes, such as spindle formation; however, the role of TP53BP1 in oocyte meiosis is currently unclear. Our results show that TP53BP1 knockdown affects spindle bipolarity and chromatin alignment by altering MTOC stability during oocyte maturation. TP53BP1 was localized in the cytoplasm and displayed an irregular cloud pattern around the spindle/chromosome region. TP53BP1 was also required for the correct localization of MTOCs into the two spindle poles during pro-meiosis I. TP53BP1 deletion altered the MTOC-localized Aurora Kinase A. TP53BP1 knockdown caused the microtubules to detach from the kinetochores and increased the rate of aneuploidy. Taken together, our data show that TP53BP1 plays crucial roles in chromosome stability and spindle bipolarity during meiotic maturation.
Assuntos
Cromossomos de Mamíferos/metabolismo , Cinetocoros/metabolismo , Meiose , Oócitos/metabolismo , Fuso Acromático/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Animais , Aurora Quinase A/metabolismo , Citoplasma/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos ICR , Oócitos/citologiaRESUMO
Gastric cardia adenocarcinoma (GCA) is one of the most common malignant tumors and among the leading causes of cancer-related death. Genetic factors might play an important role in GCA carcinogenesis. Here, we performed a hospital-based case-control study to evaluate the effect of functional p21, p53, TP53BP1 and p73 single nucleotide polymorphisms (SNPs) on the risk of GCA. The study included 330 GCA cases and 608 controls. Genotypes were determined using the ligation detection reaction (LDR) method. The p21 rs1059234 TT, p21 rs3176352 GC/CC, p21 rs762623 GA and TP53BP1 rs560191 CC genotypes were associated with the risk of GCA, and a genotype combination effect was observed. After Bonferroni correction, the association remained significant for TP53BP1 rs560191 G > C, whereas the remaining four SNPs showed no association between the polymorphisms and GCA risk in all comparison models. Further large replication studies are needed to confirm the present findings.
Assuntos
Adenocarcinoma/genética , Cárdia/patologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adenocarcinoma/etnologia , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , China , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas de Ligação a DNA/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fatores de Risco , Neoplasias Gástricas/etnologia , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53RESUMO
OBJECTIVE: To investigate the association between gastric cardia adenocarcinoma (GCA) and ten functional single nucleotide polymorphisms (SNPs), including TP53BP1 rs560191 G>C, CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A, and six C1orf10/CRNN variants. We performed a hospital-based case-control study to evaluate the genetic effects of these SNPs. METHODS: Two hundred and forty-three GCA cases and 476 controls were enrolled in this study. A custom-by-design 48-Plex SNPscan(TM) Kit was used to determine their genotypes. RESULTS: When the TP53BP1 rs560191 GG homozygote genotype was used as the reference group, the GC genotype was associated with a significantly increased risk of GCA. The CC genotype was not associated with the risk of GCA compared with the GG genotype. None of the CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A or the six C1orf10/CRNN polymorphisms showed a significant difference in genotype distributions between the cases and the controls. CONCLUSIONS: The results demonstrated that the functional polymorphism TP53BP1 rs560191 G>C might contribute to GCA susceptibility. However, the statistical power of our study was limited. Large, well-designed studies and further functional investigations are needed to confirm our findings.
RESUMO
BACKGROUND: Lymph node (LN) metastases increase the risk of death from prostate cancer (CaP). The dysfunction of factors responsible for DNA injury detection may promote the evolution of localized primary tumors into the metastatic form. METHODS: In this study, 52 cases of CaP were analyzed. The cases were divided into groups of CaP without metastases (N0), with metastases to the LNs (N+), and metastatic LN tissue. Immunohistochemical examinations were performed with antibodies against MDC1, TP53BP1, MLH1, MSH2, MSH6, and PMS2. RESULTS: Statistical analysis showed lower nuclear expression of TP53BP1 in N+ cases than in N0 cases (Pâ¯=â¯0.026). Nuclear TP53BP1 expression was lower in LN cases than in N+ cases (Pâ¯=â¯0.019). Statistical analysis showed lower nuclear expression of MLH1 in N+ cases than in to N0 cases (Pâ¯=â¯0.003). CONCLUSION: Decreased expression of both MLH1 and TP53B1 were demonstrated in N+ cases of CaP. This observation could help to determine the risk of nodal metastasis, and to select appropriate treatment modalities for patients with locally advanced CaP.
Assuntos
Metástase Linfática , Proteína 1 Homóloga a MutL/fisiologia , Neoplasias da Próstata/patologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/fisiologia , Idoso , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 C-terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of 7 tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples. Tumors with worse prognosis (tumor grade 3 and triple negative) showed reduced expression of tBRCT genes, notably, PAXIP1 and TP53BP1. Survival analyses data indicated that tumor status of both genes may impact prognosis. PAXIP1 and 53BP1 protein levels followed gene expression results, i.e., are intrinsically correlated, and also reduced in more advanced tumors. Evaluation of both genes in triple negative breast tumor samples which were characterized for their BRCA1 status showed that PAXIP1 is overexpressed in BRCA1 mutant tumors. Taken together our findings indicate that PAXIP1 status correlates with breast cancer staging, in a manner similar to what has been characterized for TP53BP1.