Inheritance of one defective BRCA2 allele predisposes humans to breast cancer. To establish a mouse model for BRCA2-associated breast cancer, we generated mouse conditional mutants with BRCA2 and/or p53 inactivated in various epithelial tissues, including mammary-gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of one wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. Our results show that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer.

Small cell lung cancer (SCLC) is a highly aggressive human tumor with a more than 95% mortality rate. Its ontogeny and molecular pathogenesis remains poorly understood. We established a mouse model for neuroendocrine (NE) lung tumors by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. Mice carrying conditional alleles for both Rb1 and Trp53 developed with high incidence aggressive lung tumors with striking morphologic and immunophenotypic similarities to SCLC. Most of these tumors, which we designate MSCLC (murine small cell lung carcinoma), diffusely spread through the lung and gave rise to extrapulmonary metastases. In our model, inactivation of both Rb1 and p53 was a prerequisite for the pathogenesis of SCLC.

Plants were grown in the greenhouse or in the field under standard conditions. We used the B73 wild-type line. For cytokinin induction experiments, 2-week-old seedlings were excised at the shoot-root junction, and stood in water supplemented with different concentrations of cytokinin. After treatments, the seedlings were dissected into a shoot fraction (apical and axillary shoot meristems, stem and 4-5 young leaf primordia) or a leaf fraction (expanding and mature leaves). For embryo culture experiments, pollinated ears at either 13 days after pollination (first leaf stage) or 16 days after pollination (second to third leaf stage) were sterilized in 30% commercial bleach solution for 20 min then rinsed five times with sterile water. The embryos were dissected out and cultured on maize embryo culture medium (1 £ Murashige and Skoog salts, 1 £ Gamborg's vitamins, 2% sucrose, 0.7% agar, pH 5.7) in some cases with the addition of cytokinin (kinetin, 10 25

Small cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic Ras(V12). Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties.

Synaptonemal complexes (SCs) are structures that are formed between homologous chromosomes during meiotic prophase. They are probably involved in chromosome pairing and recombination. Using a monoclonal anti‐SC antibody we isolated cDNAs encoding a major component of SCs which is localized specifically in synapsed segments of meiotic prophase chromosomes. The protein predicted from the nucleotide sequence of a full‐length cDNA, named SCP1, consists of 946 amino acid residues and has a molecular weight of 111 kDa. It shares several features with nuclear lamins and some recently identified nuclear matrix proteins. The major part of SCP1 consists of long stretches capable of forming amphipathic alpha‐helices. This region shows amino acid sequence similarity to the coiled‐coil region of myosin heavy chain. A leucine zipper is included in this region. The carboxy‐terminus has two small basic domains and several S/T‐P‐X‐X motifs, which are characteristic of DNA‐binding proteins. One of these motifs is a potential target site for p34cdc2 protein kinase. The amino‐terminus is acidic and relatively proline‐rich, but does not contain the S/T‐P‐X‐X motif. The transcription of the gene encoding SCP1 is restricted to zygotene‐diplotene spermatocytes. A polyclonal antiserum raised against the fusion protein of one of the cDNA clones recognizes a single protein on Western blots of isolated SCs, with an electrophoretic mobility identical to that of the antigen recognized by the original monoclonal antibody (mAb), IX5B2. From a detailed comparison of the immunogold labelling of rat SCs by mAb IX5B2 and the polyclonal anti‐fusion protein antiserum respectively, we tentatively infer that the carboxy‐terminus of SCP1 is orientated towards the lateral elements and that the other domains of the protein extend towards the central region between the lateral elements. We conclude that SCP1 is the major component of the transverse filaments of SCs, and speculate that it has evolved by specialization of a nuclear matrix protein.