Viral oncogene-induced DNA damage response is activated in Kaposi sarcoma tumorigenesis
| Autor: | Päivi M. Ojala, Pawan Pyakurel, Annika Järviluoma, Johanna Furuhjelm, Marikki Laiho, Maria Wirzenius, Sari Jäämaa, Christel Pussinen, Peter Biberfeld, Kari Alitalo, Sonja Koopal |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Skin Neoplasms
DNA damage QH301-705.5 viruses Immunology Viral Oncogene Biology medicine.disease_cause Biochemistry Microbiology Virus S Phase Viral Proteins 03 medical and health sciences 0302 clinical medicine Homo (Human) Virology Genetics medicine Humans Biology (General) Sarcoma Kaposi Molecular Biology 030304 developmental biology Centrosome 0303 health sciences Cell Cycle DNA replication Endothelial Cells virus diseases Cell Biology Cell cycle G2-M DNA damage checkpoint RC581-607 medicine.disease 3. Good health Infectious Diseases Oncology 030220 oncology & carcinogenesis DNA Viral Herpesvirus 8 Human Viruses Cancer research Parasitology Sarcoma Immunologic diseases. Allergy Carcinogenesis DNA Damage Research Article |
| Zdroj: | PLoS Pathogens, Vol 3, Iss 9, Pp 1348-1360 (2007) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Kaposi sarcoma is a tumor consisting of Kaposi sarcoma herpesvirus (KSHV)–infected tumor cells that express endothelial cell (EC) markers and viral genes like v-cyclin, vFLIP, and LANA. Despite a strong link between KSHV infection and certain neoplasms, de novo virus infection of human primary cells does not readily lead to cellular transformation. We have studied the consequences of expression of v-cyclin in primary and immortalized human dermal microvascular ECs. We show that v-cyclin, which is a homolog of cellular D-type cyclins, induces replicative stress in ECs, which leads to senescence and activation of the DNA damage response. We find that antiproliferative checkpoints are activated upon KSHV infection of ECs, and in early-stage but not late-stage lesions of clinical Kaposi sarcoma specimens. These are some of the first results suggesting that DNA damage checkpoint response also functions as an anticancer barrier in virally induced cancers. Author Summary Recent findings have indicated that DNA hyper-replication triggered by oncogenes can induce cellular senescence, which together with the oncogene-induced DNA damage checkpoint confers a barrier to tumorigenesis. Kaposi sarcoma herpesvirus (KSHV) can infect human dermal microvascular endothelial cells (ECs) in vitro, but KSHV infection does not seem to provide growth advantage to the cells, but rather leads to retarded growth. Moreover, the proliferative index has long been known to be low in KSHV-infected spindle cells in Kaposi sarcoma (KS) tumors. Our results provide an explanation for these observations by showing that activation of the DNA damage response, exerted by KSHV and a latent viral protein v-cyclin, functions as a barrier against transformation of KSHV-infected cells. Interestingly, the antiproliferative checkpoints are activated during the initial stages of KSHV infection and KS tumorigenesis. During the course of infection, the infected cells are imposed to overcome the checkpoint, and oncogenic stress elicited by the expression of v-cyclin may further contribute to the induction of genomic instability and malignant transformation. |
| Databáze: | OpenAIRE |
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