ABSTRACT
Itch is a member of the HECT family of ubiquitin E3 ligases, and regulates the stability of several proteins involved in response to genotoxic stress. We have previously shown that p73 and p63, two members of the p53 family of tumour suppressors, are targets for Itch-mediated ubiquitylation and degradation. Here, we show that depletion of Itch by RNA interference augments apoptosis upon treatment with chemotherapeutic drugs. We also show that cells with no functional p53 are more sensitive to Itch depletion, highlighting the importance that changes in levels of Itch may play in majority of cancers, where p53 is absent or mutated. Furthermore, reintroduction of Itch in fibroblasts obtained from Itch deficient mice results in reduced cell death upon DNA damage. Overall our findings suggest that inhibition of Itch potentiates the effect of chemotherapeutic drugs revealing the pharmacological potentials of targeting Itch for cancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Repressor Proteins/antagonists & inhibitors , Ubiquitin-Protein Ligases/antagonists & inhibitors , Animals , Apoptosis , Cell Line, Tumor , HeLa Cells , Humans , Mice , Mice, Knockout , RNA Interference , Repressor Proteins/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
Replicative senescence is thought to be an intrinsic mechanism for limiting the proliferative life-span of normal somatic cells. We show here that rat Schwann cells can be expanded indefinitely in culture while maintaining checkpoints normally lost during the immortalization process. These findings demonstrate that senescence is not an inevitable consequence of extended proliferation in culture.
Subject(s)
Cell Division , Cellular Senescence , Schwann Cells/cytology , Animals , Blood , Carrier Proteins/metabolism , Cell Culture Techniques , Cell Line , Cell Size , Cells, Cultured , Clone Cells , Culture Media , Cyclin-Dependent Kinase Inhibitor p16 , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Fibroblasts/cytology , Fibroblasts/physiology , Giant Cells/cytology , Mutation , Phenotype , Proteins/metabolism , Rats , Schwann Cells/physiology , Telomerase/metabolism , Telomere/physiology , Tumor Suppressor Protein p14ARF , Tumor Suppressor Protein p53/metabolism , beta-Galactosidase/metabolism , ras Proteins/metabolismABSTRACT
Historically, the senescent state has been associated with, and was named after, the cell-cycle arrest that occurs after cells have undergone an intrinsically defined number of divisions in vitro. More recently, however, it has been shown that extrinsic factors, including those encountered in normal tissue-culture environments, can prematurely induce an indistinguishable senescent phenotype. In this review, we discuss the pathways of cell senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer.
Subject(s)
Cellular Senescence/physiology , Neoplasms/pathology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Transformation, Neoplastic/genetics , DNA Damage , DNA Replication , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Fibroblasts/cytology , Humans , Mice , Mice, Knockout , Models, Genetic , Neoplasm Proteins/physiology , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/genetics , Phenotype , RNA/genetics , Telomerase/deficiency , Telomerase/genetics , Telomerase/physiology , Telomere/ultrastructureABSTRACT
BACKGROUND: Papuloerythroderma of Ofuji is an uncommon condition characterized by diffuse pruriginous eruptions of infiltrating papulae. The large folds are not involved. The eruptions are associated with lymphopenia and eosinophilia. Very few cases have been reported in the literature and because of their heterogeneous nature, there is some debate as to whether this is a single clinical entity or a particular presentation of erythrodermia; Immunomodulation is recommended. CASE REPORT: A 73 year-old man of asian origin living in France presented chronic pruriginous erythrodermia with flat purplish-brown confluent papulae which did not involve the large folds. Eosophilia and lymphopenia were present. The biopsy specimen evidenced dermal infiltration with CD4+CD45+RO+ T cells, eosinophils and DC1a+ dendritic cells. Further explorations did not reveal any sign favoring lymphoma, carcinoma or underlying infection. Dermocorticoids, PUVA-therapy and interferon-alpha were ineffective. Considerable clinical improvement was obtained with cyclosporine A. DISCUSSION: We used ciclosporine A in our patient after repeated failure of other therapies reported to be effective in this dermatosis. Despite the favorable outcome, this therapeutic approach should be used with prudence.
Subject(s)
Cyclosporine/therapeutic use , Dermatitis, Exfoliative/drug therapy , Dermatologic Agents/therapeutic use , Immunosuppressive Agents/therapeutic use , Skin Diseases, Vesiculobullous/drug therapy , Aged , CD4-Positive T-Lymphocytes/pathology , Dendritic Cells/pathology , Dermatitis, Exfoliative/pathology , Eosinophilia/pathology , Humans , Interferon-alpha/therapeutic use , Langerhans Cells/pathology , Lymphopenia/pathology , Male , PUVA Therapy , Prurigo/pathology , Skin Diseases, Vesiculobullous/pathology , T-Lymphocytes/pathology , Treatment OutcomeABSTRACT
INTRODUCTION: We report the first case of bilateral neurofibromatosis localized distally on the lower limbs. CASE REPORT: A 36-year-old woman presented about 20 nodular lesions of the plantar and both lateral aspects of both feet which developed progressively after age 30. Histology examination evidenced neurofibromas. Clinical features and laboratory results enabled us to eliminate von Recklinghausen disease in this mother of 3 children. DISCUSSION: This observation allowed us to situate symmetrical and bilateral neurofibromatosis in the Riccardi classification for genetic counselling. We conclude that the case was a type V neurofibromatosis in a sporadic bilateral form, rarely reported in the literature.
