Functional analyses of a human vascular tumor FOS variant identify a novel degradation mechanism and a link to tumorigenesis

Abstract

Edited by Alex Toker Epithelioid hemangioma is a locally aggressive vascular neoplasm, found in bones and soft tissue, whose cause is currently unknown, but may involve oncogene activation. FOS is one of the earliest viral oncogenes to be characterized, and normal cellular FOS forms part of the activator protein 1 (AP-1) transcription factor complex, which plays a pivotal role in cell growth, differentiation, and survival as well as the DNA damage response. Despite this, a causal link between aberrant FOS function and naturally occurring tumors has not yet been established. Here, we describe a thorough molecular and biochemical analysis of a mutant FOS protein we identified in these vascular tumors. The mutant protein lacks a highly conserved helix consisting of the C-terminal four amino acids of FOS, which we show is indispensable for fast, ubiquitin-independent FOS degradation via the 20S proteasome. Our work reveals that FOS stimulates endothelial sprouting and that perturbation of normal FOS degradation could account for the abnormal vessel growth typical of epithelioid hemangioma. To the best of our knowledge, this is the first functional characterization of mutant FOS proteins found in tumors.

Molecular Pathology of Bone Tumors

“…This mutant protein is indispensable for fast, ubiquitinindependent FOS degradation, and as FOS stimulates endothelial sprouting, disrupted degradation of mutant FOS protein could account for the abnormal vessel growth in epithelioid hemangioma. 17,45 Also, recurrent rearrangements of FOS and its paralog FOSB were recently found in osteoblastoma. Whereas the FOSB translocation led to substitution of the promoter, tumorigenesis in FOS-translocated osteoblastoma may be stimulated by the same mechanism of disrupted degradation of FOS.…”

Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma

“…Western blotting and IHC have previously been described by our group (13). Antibodies were obtained from the following sources: Flag monoclonal rabbit antibody (F7425; Sigma); FOS Research.…”

FOS-ANKH and FOS-RUNX2 Fusion Genes in Osteoblastoma

“…The amount of FOS protein in cells is tightly regulated at the transcriptional and translational levels and by interaction between transcription and translation (17)(18)(19)(20). In the 3'untranslated region (3'-UTR), there are two domains of AUrich elements involved in the stability of FOS mRNA, a localization signal which binds the mRNA to the perinuclear cytoskeleton, a sequence that binds the miR-7b miRNA decreasing mRNA translation, and AU-rich regions which interact with parts of FOS coding regions facilitating mRNA deadenylation (poly(A) tail-shortening process) and decay by a mechanism coupled to translation (17,19,(21)(22)(23)(24)(25)(26)(27).…”

“…FOS is an unstable, easily degradable protein. The carboxy terminal part of FOS was found to be essential for FOS protein degradation (18,20,(28)(29)(30)(31)(32). (8,33,34).…”

“…The resulting, truncated FOS protein contains the Nterminal transactivation domain, which plays a crucial role in transformation, and the basic leucine zipper domain (bZIP) making it more stable than wild-type FOS (8,20,(33)(34)(35). In vitro experiments have shown that truncated FOS protein is resistant to degradation and has a longer half-life than the wild-type FOS protein (circa 1-2 h) (20).…”