Commitment Complex Splicing Factors in Cancers of the Gastrointestinal Tract-An In Silico Study.

The initial step in pre-mRNA splicing involves formation of a spliceosome commitment complex (CC) or E-complex by factors that serve to bind and mark the exon-intron boundaries that will undergo splicing. The CC component U1 snRNP assembles at the 5'-splice site (ss), whereas SF1, U2AF2, and U2AF1 define the 3'-ss of the intron. A PRP40 protein bridges U1 snRNP with factors at the 3'-ss.

analysis of DND1 and its co-expressed genes in human cancers.

Dead-End (DND1) is an RNA-binding protein involved in translational regulation. Defects in gene causes germ cell tumors and sterility in rodents. Experimental studies with human somatic cancer cells indicate that DND1 has anti-proliferative and pro-apoptotic function in some while oncogenic function in other cells.

The Role of DND1 in Cancers.

The mutation in Dead-End 1 (), , which leads to a premature stop codon, has been determined to be the cause for primordial germ cell deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas in the 129/Sv- mice. As an RNA-binding protein, DND1 can bind the 3'-untranslated region (3'-UTR) of mRNAs and function in translational regulation. DND1 can block microRNA (miRNA) access to the 3'-UTR of target mRNAs, thus inhibiting miRNA-mediated mRNA degradation and up-regulating translation or can also function to degrade or repress mRNAs.

Deficiency of Splicing Factor 1 (SF1) Reduces Intestinal Polyp Incidence in Mice.

Background: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified (or ) mice express reduced levels of SF1 protein in mouse tissues, including in cells of the intestines. Mutational inactivation of human adenomatous polyposis coli (APC) gene deregulates the signaling pathway and is a frequent genetic event in colon cancers.

Generation of a novel mouse strain with conditional, cell-type specific, expression of DND1.

Dead-End 1 (DND1) encodes an RNA binding protein critical for viable primordial germ cells in vertebrates. When introduced into cancer cell lines, DND1 suppresses cell proliferation and enhances apoptosis. However, the molecular function of mammalian wild-type DND1 has mostly been studied in cell lines and not verified in the organism.

Tumor loci and their interactions on mouse chromosome 19 that contribute to testicular germ cell tumors.

Background: Complex genetic factors underlie testicular germ cell tumor (TGCT) development. One experimental approach to dissect the genetics of TGCT predisposition is to use chromosome substitution strains, such as the 129.MOLF-Chr 19 (M19).

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling.

Clinically atypical seminomas with yolk sac tumor features.

Introduction: A small subset of young men die from seminoma. Studying these high risk, clinically atypical seminomas (CASs)-aggressive tumors with visceral metastases and chemotherapy resistance-may provide clues to the nature of drug resistance and the origin of testicular cancers. We explored the possibility that these seminomas are a unique clinical and biologic entity with intrinsic yolk sac tumor (YST) features.

APOBEC3 inhibits DEAD-END function to regulate microRNA activity.

The RNA binding protein DEAD-END (DND1) is one of the few proteins known to regulate microRNA (miRNA) activity at the level of miRNA-mRNA interaction. DND1 blocks miRNA interaction with the 3'-untranslated region (3'-UTR) of specific mRNAs and restores protein expression. Previously, we showed that the DNA cytosine deaminase, APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide like 3), interacts with DND1.

Fetal radiation exposure induces testicular cancer in genetically susceptible mice.

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.

Transcripts that associate with the RNA binding protein, DEAD-END (DND1), in embryonic stem (ES) cells.

Background: The RNA binding protein, DEAD END (DND1), is essential for maintaining viable germ cells in vertebrates. It is also a testicular germ cell tumor susceptibility factor in mice. DND1 has been shown to interact with the 3'-untranslated region (3'-UTR) of mRNAs such as P27 and LATS2.

Recurrent seminomas: clinical features and biologic implications.

Objectives: Certain patients with seminoma and clinically atypical phenotypes--visceral metastases, elevated levels of β human chorionic gonadotropin (βHCG), and/or recurrent disease--have a poor prognosis. The primary goal of this pilot study was to characterize the clinical characteristics and treatment profile of these rare patients. We also wished to test whether these tumors expressed any specific biomarkers that might distinguish them as a unique subtype of seminoma.

Deficiency of splicing factor 1 suppresses the occurrence of testicular germ cell tumors.

Testicular germ cell tumors (TGCT) originate from germ cells. The 129-Ter and M19 (129.MOLF-Chr19 consomic) mouse strains have extremely high incidences of TGCTs.

The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency.

Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. Here, we show that in mice of the 129Sv strain, loss of Dmrt1 causes a high incidence of teratomas, whereas these tumors do not form in Dmrt1 mutant C57BL/6J mice. Conditional gene targeting indicates that Dmrt1 is required in fetal germ cells but not in Sertoli cells to prevent teratoma formation.

Tools for the genetic analysis of germ cells.

Germ cells are essential for the propagation of individual species. Studies on germ cell development in mice highlight important biological paradigms. Beginning with their first appearance around embryonic day 7 (E7), germ cells undergo specific cellular changes at different stages of their embryonic and adult development.

WDR55 is a nucleolar modulator of ribosomal RNA synthesis, cell cycle progression, and teleost organ development.

The thymus is a vertebrate-specific organ where T lymphocytes are generated. Genetic programs that lead to thymus development are incompletely understood. We previously screened ethylnitrosourea-induced medaka mutants for recessive defects in thymus development.

Mouse apolipoprotein B editing complex 3 (APOBEC3) is expressed in germ cells and interacts with dead-end (DND1).

Background: The dead-end (Dnd1) gene is essential for maintaining the viability of germ cells. Inactivation of Dnd1 results in sterility and testicular tumors. The Dnd1 encoded protein, DND1, is able to bind to the 3'-untranslated region (UTR) of messenger RNAs (mRNAs) to displace micro-RNA (miRNA) interaction with mRNA.

Chromosome X modulates incidence of testicular germ cell tumors in Ter mice.

Germ cell tumor development in humans has been proposed to be part of testicular dysgenesis syndrome (TDS), which manifests as undescended testes, sterility, hypospadias, and, in extreme cases, as germ cell tumors. Males of the Ter mouse strain show interesting parallels to TDS because they either lack germ cells and are sterile or develop testicular germ cell tumors. We found that these defects in Ter mice are due to mutational inactivation of the Dead-end (Dnd1) gene.

The role of dead-end in germ-cell tumor development.

Testicular germ-cell tumors occur in human males of all age groups, from infants to men over 50 years old. Most commonly, germ-cell tumors (generally known as testicular cancer) occur in young males between the ages of 15 to 35 years. The tumor tissues are usually histologically diverse, and testicular tumors that occur in the different age groups tend to be of specific histological subtypes.

Testicular germ cell tumor susceptibility genes from the consomic 129.MOLF-Chr19 mouse strain.

Chromosome substitution strains (CSS or consomic strains) are useful for mapping phenotypes to chromosomes. However, huge efforts are needed to identify the gene(s) responsible for the phenotype in the complex context of the chromosome. Here we report the identification of candidate disease genes from a CSS by using a combination of genetic and genomic approaches and by using knowledge about the germ cell tumor disease etiology.

The mouse dead-end gene isoform alpha is necessary for germ cell and embryonic viability.

Inactivation of the dead-end (Dnd1) gene in the Ter mouse strain results in depletion of primordial germ cells (PGCs) so that mice become sterile. However, on the 129 mouse strain background, loss of Dnd1 also increases testicular germ cell tumor incidence in parallel to PGC depletion. We report that inactivation of Dnd1 also affects embryonic viability in the 129 strain.

Search for testicular cancer gene hits dead-end.

Testicular germ cell tumors (TGCTs) are the first tumors where the cell of origin, and the time of transformation were precisely defined. TGCTs in mice originate from primordial germ cells (PGCs) and develop within the testis during fetal development. TGCTs occur at an appreciable frequency (5%) only in the 129 family of inbred strains of laboratory mice, suggesting strong genetic control.

The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours.

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells, and after birth differentiate into various cells and tissues that compose TGCTs.

Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications.

Testicular germ cell tumors (TGCTs) are the most common solid cancers affecting young men. Although the evidence for genetic predisposition to TGCTs in humans is compelling, the genetic control of susceptibility is poorly understood. The 129S1/SvImJ (129/Sv) inbred strain of mice is an excellent model for studying TGCT susceptibility.