ABSTRACT
The development of specialized organs is tightly linked to the regulation of cell growth, orientation, migration and adhesion during embryogenesis. In addition, the directed movements of cells and their orientation within the plane of a tissue, termed planar cell polarity (PCP), appear to be crucial for the proper formation of the body plan. In Drosophila embryogenesis, Discs large (dlg) plays a critical role in apical-basal cell polarity, cell adhesion and cell proliferation. Craniofacial defects in mice carrying an insertional mutation in Dlgh-1 suggest that Dlgh-1 is required for vertebrate development. To determine what roles Dlgh-1 plays in vertebrate development, we generated mice carrying a null mutation in Dlgh-1. We found that deletion of Dlgh-1 caused open eyelids, open neural tube, and misorientation of cochlear hair cell stereociliary bundles, indicative of defects in planar cell polarity (PCP). Deletion of Dlgh-1 also caused skeletal defects throughout the embryo. These findings identify novel roles for Dlgh-1 in vertebrates that differ from its well-characterized roles in invertebrates and suggest that the Dlgh-1 null mouse may be a useful animal model to study certain human congenital birth defects.
Subject(s)
Bone and Bones/embryology , Cell Polarity/genetics , Embryonic Development/genetics , Guanylate Kinases/genetics , Membrane Proteins/genetics , Animals , Bone and Bones/pathology , Cell Adhesion/genetics , Cell Proliferation , Discs Large Homolog 1 Protein , Eyelids/growth & development , Eyelids/pathology , Germ-Line Mutation , Humans , Mice , Mice, Knockout , Mutation , Neural Tube/growth & development , Neural Tube/pathology , Vertebrates/genetics , Vertebrates/growth & developmentABSTRACT
The deubiquitinating enzyme CYLD is a tumor suppressor protein known for its role in repression of generally pro-oncogenic NF-kappaB activation pathways. Two new studies published in this and the September issue of Developmental Cell show that CYLD dismantles distinct types of polyubiquitin chains formed on select signaling proteins and is thereby required for normal vertebrate and invertebrate development.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Cysteine Endopeptidases/physiology , Drosophila Proteins/physiology , Tumor Suppressor Proteins/physiology , Animals , Cysteine Endopeptidases/genetics , Deubiquitinating Enzyme CYLD , Drosophila/genetics , Drosophila/physiology , Drosophila Proteins/genetics , Humans , Mice , NF-kappa B/metabolism , Polyubiquitin/metabolism , Signal Transduction , Tumor Suppressor Proteins/geneticsABSTRACT
High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6(WT)) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6(WT) mice with those of K14E6(delta146-151) mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6(delta146-151) transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6(WT) mice, they are infrequently seen in tumors arising on K14E6(delta146-151) mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53.
