FBXO4 opposes cyclin D1 accumulation and the tumorigenic potential of BRAF(V600E) in melanoma [electronic resource].

Lee, Eric.
199 p.
Local subjects:
Biology, Cell.
System Details:
Mode of access: World Wide Web.
Dysregulation of cell cycle factors, such as cyclin D1, is a critical step in tumorigenesis. Increased cyclin D1 expression in cancer has been attributed to gene amplification, translocations, and transcriptional activation; however, the role of impaired proteolysis leading to cyclin D1 accumulation in cancer has not been extensively studied. SCFFBXO4 is a ubiquitin ligase that mediates degradation of phosphorylated cyclin D1 following the G1-S phase transition. Genetic screens in human esophageal cancer with elevated cyclin D1 revealed loss-of-function dimerization FBXO4 mutations. I show that these FBXO4 mutations impact the critical interaction with the 14-3-3ϵ regulatory protein required for maximal ubiquitylation efficiency. I demonstrate in vivo that Fbxo4 acts as a tumor suppressor and loss of Fbxo4 predisposes mice to a variety of cyclin D1-overexpressing tumor types. Furthermore, my work reveals that Fbxo4-deficiency in the context of somatic melanocyte-specific B-raf V600E activation dramatically enhances the occurrence of melanoma in a cyclin D1-dependent manner. Our human melanoma screens revealed the presence of an I377M mutation in the C-terminal of FBXO4. My data indicate that FBXO4 I377M exhibits loss-of-function properties with regard to cyclin D1 regulation. Intriguingly, FBXO4 I377M retains its ability to regulate another substrate TRF1.
Finally, I present evidence that the well-known melanoma driver mutation B-RAFV600E suppresses DNA damage and regulates a chromatin mark governing the balance between DNA repair and apoptosis, a previously unappreciated role that carries treatment implications and could open new therapeutic avenues.
Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.
Adviser: J. Alan Diehl.
Thesis (Ph.D.)--University of Pennsylvania, 2012.
Local notes:
School code: 0175.
University of Pennsylvania. Cell and Molecular Biology.
Contained In:
Dissertation Abstracts International 74-06B(E).
Access Restriction:
Restricted for use by site license.
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