E2F1 and E2F7 regulate gastric cancer cell proliferation, respectively, through transcriptional activation and transcriptional repression of MYBL2.

Gastric cancer (GC) is the most common malignant tumor of the digestive tract. However, the molecular pathogenesis is not well understood. Through bioinformatic analysis and analyzing clinical tissue samples, we found that E2F1 and E2F7 as well as their potential downstream target MYBL2 were all upregulated in GC tissues and that their expressions correlated with patient prognosis.

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.

Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children.

Granzyme B and perforin produced by SEC2 mutant-activated human CD4 T cells and CD8 T cells induce apoptosis of K562 leukemic cells by the mitochondrial apoptotic pathway.

Staphylococcal enterotoxin C2 (SEC2), a classical representative of superantigens, activates T cells that produce massive cytokines. This characteristic makes SEC2 a promising candidate drug for cancer immunotherapy. Previous study showed that ST-4, a SEC2 mutant, enhanced recognition of mouse T-cell receptor Vβ regions, and activated the increased number of T cells that produced more cytokines.

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer.

Gastric cancer is the most common malignant tumor in the digestive tract, with very high morbidity and mortality in developing countries. The pathogenesis of gastric cancer is a complex biological process mediated by abnormal regulation of proto-oncogenes and tumor suppressor genes. Although there have been some in-depth studies on gastric cancer at the molecular level, the specific mechanism has not been fully elucidated.

Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis.

DNA methyltransferase 3A (DNMT3A) catalyzes cytosine methylation of mammalian genomic DNA. In addition to myeloid malignancies, mutations in DNMT3A have been recently reported in T-cell lymphoma and leukemia, implying a possible involvement in the pathogenesis of human diseases. However, the role of Dnmt3a in T-cell transformation in vivo is poorly understood.

ERBB2 increases metastatic potentials specifically in androgen-insensitive prostate cancer cells.

Despite all the blood-based biomarkers used to monitor prostate cancer patients, prostate cancer remains as the second common cause of cancer mortality in men in the United States. This is largely due to a lack of understanding of the molecular pathways that are responsible for the aggressive forms of prostate cancers, the castrate-resistant prostate cancer and the metastatic prostate cancer. Cell signaling pathways activated by the ERBB2 oncogene or the RAS oncogene are frequently found to be altered in metastatic prostate cancers.

Inactivation of Rb and E2f8 synergizes to trigger stressed DNA replication during erythroid terminal differentiation.

Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia.

Essential role for Dnmt1 in the prevention and maintenance of MYC-induced T-cell lymphomas.

DNA cytosine methylation is an epigenetic modification involved in the transcriptional repression of genes controlling a variety of physiological processes, including hematopoiesis. DNA methyltransferase 1 (Dnmt1) is a key enzyme involved in the somatic inheritance of DNA methylation and thus plays a critical role in epigenomic stability. Aberrant methylation contributes to the pathogenesis of human cancer and of hematologic malignancies in particular.

Concomitant inactivation of Rb and E2f8 in hematopoietic stem cells synergizes to induce severe anemia.

The retinoblastoma (Rb) tumor suppressor plays important roles in regulating hematopoiesis, particularly erythropoiesis. In an effort to understand whether Rb function can be mediated by E2F transcription factors in a BM-derived hematopoietic system in mice, we uncovered a functional synergy between Rb and E2F8 to promote erythropoiesis and to prevent anemia. Specifically, whereas Mx1-Cre-mediated inactivation of Rb or E2f8 in hematopoietic stem cells only led to mild erythropoietic defects, concomitant inactivation of both genes resulted in marked ineffective erythropoiesis and mild hemolysis, leading to severe anemia despite the presence of enhanced extramedullary erythropoiesis.

E2f3a and E2f3b contribute to the control of cell proliferation and mouse development.

The E2f3 locus encodes two Rb-binding gene products, E2F3a and E2F3b, which are differentially regulated during the cell cycle and are thought to be critical for cell cycle progression. We targeted the individual inactivation of E2f3a or E2f3b in mice and examined their contributions to cell proliferation and development. Chromatin immunoprecipitation and gene expression experiments using mouse embryo fibroblasts deficient in each isoform showed that E2F3a and E2F3b contribute to G(1)/S-specific gene expression and cell proliferation.

Mouse development with a single E2F activator.

The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions. Whereas C. elegans and Drosophila melanogaster have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins.

Rb is critical in a mammalian tissue stem cell population.

The inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 (E15.5).

E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop.

E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21(CIP1). Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation.

Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations.

We previously identified a rearrangement of mixed-lineage leukemia (MLL) gene (also known as ALL-1, HRX, and HTRX1), consisting of an in-frame partial tandem duplication (PTD) of exons 5 through 11 in the absence of a partner gene, occurring in approximately 4%-7% of patients with acute myeloid leukemia (AML) and normal cytogenetics, and associated with a poor prognosis. The mechanism by which the MLL PTD contributes to aberrant hematopoiesis and/or leukemia is unknown. To examine this, we generated a mouse knockin model in which exons 5 through 11 of the murine Mll gene were targeted to intron 4 of the endogenous Mll locus.

Rb regulates proliferation and rod photoreceptor development in the mouse retina.

The retinoblastoma protein (Rb) regulates proliferation, cell fate specification and differentiation in the developing central nervous system (CNS), but the role of Rb in the developing mouse retina has not been studied, because Rb-deficient embryos die before the retinas are fully formed. We combined several genetic approaches to explore the role of Rb in the mouse retina. During postnatal development, Rb is expressed in proliferating retinal progenitor cells and differentiating rod photoreceptors.

Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice.

Retinoblastoma (Rb)-deficient embryos show severe defects in neurogenesis, erythropoiesis, and lens development and die at embryonic day 14.5. Our recent results demonstrated a drastic disorganization of the labyrinth layer in the placenta of Rb-deficient embryos, accompanied by reduced placental transport function.

Extra-embryonic function of Rb is essential for embryonic development and viability.

The retinoblastoma (Rb) gene was the first tumour suppressor identified. Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis and widespread developmental defects, leading to embryonic death by day 14.5 (refs 2-4).

Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb.

The Rb/E2F pathway plays a critical role in the control ofcellular proliferation. Here, we report that E2F1, E2F2, and E2F3 make major individual contributions toward the in vivo phenotypic consequences of Rb deficiency. In the developing lens of Rb(-/-) embryos, loss of E2F1, E2F2, or E2F3 reduces the unscheduled proliferation of fiber cells, with the loss of E2F3 having the most pronounced effect.