p53 deficiency and misexpression of protein kinase CK2alpha collaborate in the development of thymic lymphomas in mice.

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with many substrates, some of which are involved in cell cycle regulation. CK2 activity is elevated in human solid tumors and leukemia, and dysregulated expression of CK2 induces lymphoma in transgenic mice. Mice that are deficient in p53 also develop lymphomas, and p53 activity may be regulated by CK2 phosphorylation.

Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine.

IP-10 is a member of the alpha or cysteine-X amino acid-cysteine (CXC) chemokine family of chemotactic cytokines. High levels of IP-10 expression have been detected in a number of chronic human inflammatory conditions, including psoriasis, a common inflammatory disease of the skin. IP-10 has been shown to chemoattract activated T cells, inhibit the proliferation of endothelial cells, and inhibit the growth of tumors in vivo.

CD44v(3,8-10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.

In the present study, we have employed a unique breast cancer cell line (Met-1, which was derived from a high metastatic potential tumor in transgenic mice expressing polyomavirus middle T oncogene) to study the role of CD44 variant isoform(s) in the regulation of metastatic breast tumor cell behavior. The results of reverse transcriptase-polymerase chain reaction, Southern blot, nucleotide sequencing, immunoprecipitation, and immunoblot analyses indicated that these cells express a major CD44 isoform (molecular weight approximately 260 kDa) containing a v3,8-10 exon insertion (designated as CD44v3,8-10). In addition, we have determined that CD44v3,8-10 binds specifically to the cytoskeletal proteins such as ankyrin.

Word search performance for diagnoses of equine surgical colics in free-text electronic patient records.

The objectives of the current project were to: (1) identify limitations of search sensitivity and positive predictive value (PPV) for free-text surgical diagnoses included in electronic patient records maintained at the University of California, Davis, Veterinary Medical Teaching Hospital (VMTH), (2) develop procedural or programmable recommendations for removing these limitations, and (3) provide guidelines for effective search strategies for users performing aggregate searches using the VMTH clinical information system. Search sensitivity corresponds to detection sensitivity (the capacity of a search term to 'identify' a relevant document) and search PPV indicates the proportion of retrieved documents that are relevant. All horses submitted to the VMTH for a gastrointestinal (GI) disorder requiring surgical intervention in 1995 were identified using procedure codes for billing purposes and stored in the electronic patient record.

The induction of uterine leiomyomas and mammary tumors in transgenic mice expressing polyomavirus (PyV) large T (LT) antigen is associated with the ability of PyV LT antigen to form specific complexes with retinoblastoma and CUTL1 family members.

The inactivation of certain tumor suppressor genes is thought to play an important role in the genesis of a number of tumor types. For example, inactivation of the Retinoblastoma (Rb) tumor suppressor is frequently observed in a proportion of sporadic human breast cancers. While these studies suggest that inactivation of key tumor suppressor genes may play an important role in the induction of mammary cancers, direct evidence supporting this contention is lacking.

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway.

Differential expression of the neu transgene in murine mammary tissues.

The mammary glands of control FVB and mice with MTV-LTR promoted transgenes were stained using immunohistochemistry to detect neu expression. Neu expression in the terminal end buds of developing mammary glands and during early pregnancy in FVB mice was confirmed by in situ hybridization. Neu was expressed in all tumors from mice with the neu transgene but not in tumors expressing transforming growth factor alpha (TGF alpha) or polyoma virus middle T (PyV-MT).

Microcirculation and metastasis in a new mouse mammary tumor model system.

Two new metastatic mouse mammary tumor transplant lines have been established in nude mice. The Met-1 line, with the polyoma virus middle T (PyV-MT) transgene, metastasized with 100% efficiency. The Db-7 line, expressing a PyV-MT transgene mutated at positions 315 and 322, metastasized with 8.

Neoplastic transformation of prostatic and urogenital epithelium by the polyoma virus middle T gene.

Male transgenic mice expressing the polyomavirus middle T (PyV-MT) gene exhibited growth and developmental abnormalities in prostatic and other urogenital epithelium. Expression of PyV-MT was directed to these tissues by a novel, androgen-inducible expression vector based on the rat C3(1) gene. Epithelial growth disturbances (hyperplasia, dysplasia, and invasive carcinoma) were observed in the ventral and dorsal prostate, coagulating gland, epididymis, and vas deferens.

Synergistic interaction of the Neu proto-oncogene product and transforming growth factor alpha in the mammary epithelium of transgenic mice.

Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-alpha) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-alpha, we examined whether coexpression of TGF-alpha and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-alpha or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-alpha and neu in the mammary epithelium.

Deregulated expression of c-myc in megakaryocytes of transgenic mice increases megakaryopoiesis and decreases polyploidization.

Platelets, essential for vascular integrity and hemostasis, fragment from polyploid megakaryocytes, characterized by their endomitotic cell cycle. We studied the influence of overexpression of c-myc oncogene on megakaryopoiesis and endomitosis in vivo, using transgenic mice carrying c-myc fused to the estrogen receptor under the control of the platelet factor 4 (PF4) megakaryocyte-specific promoter. The rationale behind this strategy was to obtain controlled overexpression of an active c-Myc, depending on the estrogen level in the mouse circulation.

Immunohistologic c-myc protein in benign breast disease and cancer.

We have studied the histopathology and differential distribution of the c-myc protein (Myc) in human breast tissues including 17 cases of infiltrating mammary carcinoma, 4 cases of fibroadenoma, 5 cases with fibrocystic changes, and 1 case of reduction mammoplasty (as a control). Using a sensitive immunohistochemical method on frozen tissue sections, both a rabbit polyclonal anti-c-myc antibody and a mouse monoclonal anti-c-myc antibody, H51C116, produced high levels of Myc staining in the nuclei of epithelial cells of infiltrating mammary carcinomas (30-90% of cells stained). In contrast, the nuclei of epithelial cells of fibroadenomas, and breast tissues with fibrocystic changes stained infrequently.

Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors.

Receptor tyrosine kinases are important in cell signal transduction and proliferation. Abnormal expression of tyrosine kinases often leads to malignant transformation. C-met is a tyrosine kinase receptor and its ligand is hepatocyte growth factor (HGF).

Activated neu induces rapid tumor progression.

Expression of the activated neu oncogene in transgenic mice has been associated with both the synchronous (single-step) and the stochastic (multistep) transformation of the mammary epithelium. To determine the basis for these conflicting observations, additional strains of transgenic mice carrying the activated neu oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer were produced. Activated neu transgene expression, as measured by in situ hybridization and ribonuclease protection assays, resulted in rapid conversion of the normal mammary epithelium to malignant phenotype in three independent strains of mice.

The biology of mammary transgenes: five rules.

The development of hyperplasias, dysplasias, and mammary tumors has been studied extensively in transgenic mice. It is now becoming clear that transgenes activate and participate in oncogenic pathways that govern the events surrounding neoplastic progression in transgenic mice. The oncogenic pathways control mammary growth, development, and neoplastic progression.

Induction of mammary epithelial hyperplasias and mammary tumors in transgenic mice expressing a murine mammary tumor virus/activated c-src fusion gene.

Activation of the c-Src tyrosine kinase has been implicated as an important step in the induction of mammary tumors in both mice and humans. To directly assess the effect of mammary gland-specific expression of activated c-Src, we established transgenic mice that carry a constitutively activated form of c-src under transcriptional control of the murine mammary tumor virus long terminal repeat. Female mice derived from several independent transgenic lines lactate poorly as a consequence of an impairment in normal mammary epithelial development.

C-myc protein distribution - mammary adenocarcinomas of mtv/myc transgenic mice.

Transgenic mice have been used to demonstrate that the myc transgene, fused to the murine mammary tumor virus LTR promoter, leads to development of mammary tumors. To study the role of the Myc protein in these tumors, a sensitive immunohistochemical method was used to compare the Myc protein expression in mammary tumors and normal mammary gland from two independent MTV/myc transgenic lines. The highest levels of staining for Myc were found in the epithelial cell nuclei of mammary tumors and foci of mammary hyperplasia.

Histopathology of transgenic mouse mammary tumors (a short atlas).

Mammary hyperplasias, dysplasias and tumors have been described in many strains of transgenic mice. Many of the transgenes produce characteristic disturbances of growth, development and neoplasia. The disturbances can now be classified into groups.

Comparative pathology of mammary tumorigenesis in transgenic mice.

Mammary tumors arise in transgenic mice bearing growth factors, proto-oncogenes, oncogenes and tumor suppressor genes. The tumors arise from hyperplasias. The tumor natural history and histogenesis are oncogene specific.

Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice.

Physical associations between cyclins, viral oncogenes and tumour suppressor genes imply a central role for cyclins in growth control. Cyclin D1 was identified as a candidate oncogene (PRAD1) in tumour-specific DNA rearrangements and is suspected to be a contributor to several types of neoplasms including breast cancer. Cyclin D1 also rescues G1 cyclin-defective Saccharomyces cerevisiae, and is a growth-regulated gene.

Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. KGF is secreted by stromal cells and affects epithelial but not mesenchymal cell proliferation. KGF injected intravenously was found to cause dramatic proliferation of mammary epithelium in the mammary glands of rats.

Expression of LINE-1 retrotransposons in human breast cancer.

Background: Several diseases have been linked to the insertion of human LINE-1 retrotransposons (L1Hs) into structural genes. Recently, the element has been shown to be expressed in a variety of adult and pediatric germ cell cancers, leading to speculation that L1Hs-induced insertion mutations may play a role in the etiology of some neoplasias.

Methods: An L1Hs-encoded protein (p40) was assayed in breast cancer cell lines by Western blotting and in solid tumors by immunohistochemical staining and Western blotting.

Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies.

Leukemia inhibitory factor (LIF) is a cytokine involved in embryonic and hematopoietic development. To investigate the effects of LIF on the lymphoid system, we generated a line of transgenic mice that expresses diffusible LIF protein specifically in T cells. These mice display two categories of phenotype that were not previously attributed to LIF overexpression.

Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice.

Transgenic mice expressing the polyomavirus (PyV) middle T oncogene in the mammary epithelium develop multifocal mammary tumors that metastasize with high frequency. The potent transforming activity of PyV middle T antigen can, in part, be attributed to its ability to associate with and to activate a number of c-Src family tyrosine kinases (c-Src, c-Yes, and Fyn). As a first step toward assessing the role of individual c-Src family tyrosine kinases in PyV middle T antigen-induced mammary tumorigenesis, we have crossed transgenic mice carrying the mouse mammary tumor virus (MMTV)/PyV middle T antigen fusion gene with mice bearing a disrupted c-src proto-oncogene.