ABSTRACT
The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in response to a variety of cellular stresses, such as changes in osmolarity, metabolic poisons, DNA damage, heat shock or inflammatory cytokines. We have disrupted the sek1 gene in mice using homologous recombination. Sek1(-/- )embryos display severe anemia and die between embryonic day 10.5 (E10.5) and E12.5. Haematopoiesis from yolk sac precursors and vasculogenesis are normal in sek1(-/- )embryos. However, hepatogenesis and liver formation were severely impaired in the mutant embryos and E11.5 and E12.5 sek1(-/- )embryos had greatly reduced numbers of parenchymal hepatocytes. Whereas formation of the primordial liver from the visceral endoderm appeared normal, sek1(-/-) liver cells underwent massive apoptosis. These results provide the first genetic link between stress-responsive kinases and organogenesis in mammals and indicate that SEK1 provides a crucial and specific survival signal for hepatocytes.
Subject(s)
Apoptosis , Liver/embryology , MAP Kinase Kinase 4 , Mitogen-Activated Protein Kinase Kinases , Protein Kinases/physiology , Protein Serine-Threonine Kinases/physiology , Protein-Tyrosine Kinases/physiology , Animals , DNA Damage , Gene Targeting , Hematopoiesis/genetics , Liver/cytology , Mice , Mice, Knockout , Mutagenesis , Neovascularization, Physiologic/genetics , Protein Kinases/genetics , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/geneticsABSTRACT
Mutations of the tumor suppressor gene BRCA2 are associated with predisposition to breast and other cancers. Homozygous mutant mice in which exons 10 and 11 of the Brca2 gene were deleted by gene targeting (Brca2(10-11)) die before day 9.5 of embryogenesis. Mutant phenotypes range from severely developmentally retarded embryos that do not gastrulate to embryos with reduced size that make mesoderm and survive until 8.5 days of development. Although apoptosis is normal, cellular proliferation is impaired in Brca2(10-11) mutants, both in vivo and in vitro. In addition, the expression of the cyclin-dependent kinase inhibitor p21 is increased. Thus, Brca2(10-11) mutants are similar in phenotype to Brca1(5-6) mutants but less severely affected. Expression of either of these two genes was unaffected in mutant embryos of the other. This study shows that Brca2, like Brca1, is required for cellular proliferation during embryogenesis. The similarity in phenotype between Brca1 and Brca2 mutants suggests that these genes may have cooperative roles or convergent functions during embryogenesis.
Subject(s)
Cell Division/genetics , Embryo, Mammalian/cytology , Gene Expression Regulation, Developmental , Neoplasm Proteins/genetics , Transcription Factors/genetics , Animals , BRCA2 Protein , DNA-Binding Proteins/genetics , Embryonic and Fetal Development/genetics , Female , Heterozygote , Mesoderm , Mice , Mice, Mutant Strains , Proto-Oncogene Proteins p21(ras)/genetics , Rad51 Recombinase , TrophoblastsABSTRACT
PIP: The incidence of IUD translocation varies, according to different authors, from 1/1000 to 0.1-0.5%. Translocation happens because of uterine perforation at the time of insertion; the skill and experience of the operator is paramount in avoiding such a problem. This article reports on the case of a 31 year old patient who, the day following insertion of a Gravigard IUD, was hospitalized for severe pains. Radiography revealed that the device had migrated into the left superior part of the abdomen; the IUD was removed by laparotomy. Diagnosis of a translocated IUD can be done by radiography, but often ultrasonography and hysterosalpingography are necessary; laparoscopy can be done for diagnosis and treatment at the same time. It is important to remove a translocated IUD as soon as possible, especially when it is a copper IUD, since copper may cause serious peritoneal reactions.^ieng
