Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.

Abstract

Deregulation of the evolutionarily conserved Notch signaling is highly correlated with oncogenesis. Intracellular activated Notch (ICN) is a protooncogene linked to the transcription activation of a number of cellular genes involved in cell cycle regulation, differentiation, and proliferation. Stability of ICN is tightly regulated by the Sel10-mediated ubiquitin-proteasome pathway. Sel10 can function as a negative regulator of Notch and exhibits activities of a tumor-suppressor protein. This article shows that the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) directly interacts with Sel10 and forms a complex in KSHV-infected cells. This results in suppression of ICN ubiquitination and degradation. The carboxyl terminus of LANA interacts with the F-box and WD40 domains of Sel10 and competes with ICN for binding to Sel10. This elevated level of ICN is also critical for maintaining the enhanced proliferation of KSHV-infected tumor cells. These findings describe a mechanism by which the KSHV-encoded LANA protein regulates ubiquitination of ICN mediated by the F-box component of the E3 ligase Sel10, leading to proliferation of the virus-infected cells.

• Authors: Ke Lan, Subhash C Verma, Masanao Murakami, Bharat Bajaj, Rajeev Kaul, Erle S Robertson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 41 Pg. 16287-92 (Oct 09 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17909182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Viral
• Cell Cycle Proteins
• F-Box Proteins
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• Nuclear Proteins
• Receptors, Notch
• latency-associated nuclear antigen
• Ubiquitin-Protein Ligases

Topics

• Antigens, Viral (genetics, metabolism)
• Binding Sites
• Cell Cycle Proteins (chemistry, metabolism)
• Cell Line
• Cell Proliferation
• Cell Transformation, Viral
• F-Box Proteins (chemistry, metabolism)
• F-Box-WD Repeat-Containing Protein 7
• Herpesvirus 8, Human (genetics, metabolism, pathogenicity)
• Humans
• Models, Biological
• Nuclear Proteins (genetics, metabolism)
• Protein Structure, Tertiary
• Proto-Oncogenes
• Receptors, Notch (genetics, metabolism)
• Signal Transduction
• Ubiquitin-Protein Ligases (chemistry, metabolism)
• Ubiquitination