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1.
EMBO J ; 37(23)2018 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-30158112

RESUMEN

Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG-I was responsible for such tumor-inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double-stranded RNA (dsRNA), the binding ligand of RIG-I. These up-regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre-mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well-characterized endogenous retroviruses that encode dsRNA In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down-stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.


Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo C/biosíntesis , Interferones/metabolismo , Proteínas de Neoplasias/biosíntesis , ARN Bicatenario/biosíntesis , ARN Neoplásico/biosíntesis , Regulación hacia Arriba , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Humanos , Interferones/genética , Intrones , Células MCF-7 , Ratones , Proteínas de Neoplasias/genética , Empalme del ARN , ARN Bicatenario/genética , ARN Neoplásico/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
2.
Stem Cell Reports ; 19(5): 689-709, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38701778

RESUMEN

Embryo size, specification, and homeostasis are regulated by a complex gene regulatory and signaling network. Here we used gene expression signatures of Wnt-activated mouse embryonic stem cell (mESC) clones to reverse engineer an mESC regulatory network. We identify NKX1-2 as a novel master regulator of preimplantation embryo development. We find that Nkx1-2 inhibition reduces nascent RNA synthesis, downregulates genes controlling ribosome biogenesis, RNA translation, and transport, and induces severe alteration of nucleolus structure, resulting in the exclusion of RNA polymerase I from nucleoli. In turn, NKX1-2 loss of function leads to chromosome missegregation in the 2- to 4-cell embryo stages, severe decrease in blastomere numbers, alterations of tight junctions (TJs), and impairment of microlumen coarsening. Overall, these changes impair the blastocoel expansion-collapse cycle and embryo cavitation, leading to altered lineage specification and developmental arrest.


Asunto(s)
Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio , Factores de Transcripción , Animales , Ratones , Blastocisto/metabolismo , Blastocisto/citología , Nucléolo Celular/metabolismo , Desarrollo Embrionario/genética , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias de Ratones/citología , Uniones Estrechas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Wnt/metabolismo , Vía de Señalización Wnt
3.
Cell Stem Cell ; 30(8): 1091-1109.e7, 2023 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-37541213

RESUMEN

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Factor Trefoil-2/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Páncreas/metabolismo , Células Acinares/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo
4.
Cell Rep ; 33(10): 108474, 2020 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-33296649

RESUMEN

Bi-species, fusion-mediated, somatic cell reprogramming allows precise, organism-specific tracking of unknown lineage drivers. The fusion of Tcf7l1-/- murine embryonic stem cells with EBV-transformed human B cell lymphocytes, leads to the generation of bi-species heterokaryons. Human mRNA transcript profiling at multiple time points permits the tracking of the reprogramming of B cell nuclei to a multipotent state. Interrogation of a human B cell regulatory network with gene expression signatures identifies 8 candidate master regulator proteins. Of these 8 candidates, ectopic expression of BAZ2B, from the bromodomain family, efficiently reprograms hematopoietic committed progenitors into a multipotent state and significantly enhances their long-term clonogenicity, stemness, and engraftment in immunocompromised mice. Unbiased systems biology approaches let us identify the early driving events of human B cell reprogramming.


Asunto(s)
Reprogramación Celular/genética , Células Madre Hematopoyéticas/metabolismo , Factores Generales de Transcripción/metabolismo , Animales , Linfocitos B/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Reprogramación Celular/fisiología , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Femenino , Sangre Fetal/metabolismo , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Células Madre Multipotentes/metabolismo , Factores de Transcripción/metabolismo , Factores Generales de Transcripción/genética , Factores Generales de Transcripción/fisiología
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