Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3.
Akihiro YoshidaJaewoo ChoiHong Ri JinYan LiSagar BajpaiShuo QieJ Alan DiehlPublished in: Oncogene (2020)
Overexpression of D-type cyclins in human cancer frequently occurs as a result of protein stabilization, emphasizing the importance of identification of the machinery that regulates their ubiqutin-dependent degradation. Cyclin D3 is overexpressed in ~50% of Burkitt's lymphoma correlating with a mutation of Thr-283. However, the E3 ligase that regulates phosphorylated cyclin D3 and whether a stabilized, phosphorylation deficient mutant of cyclin D3, has oncogenic activity are undefined. We describe the identification of SCF-Fbxl8 as the E3 ligase for Thr-283 phosphorylated cyclin D3. SCF-Fbxl8 poly-ubiquitylates p-Thr-283 cyclin D3 targeting it to the proteasome. Functional investigation demonstrates that Fbxl8 antagonizes cell cycle progression, hematopoietic cell proliferation, and oncogene-induced transformation through degradation of cyclin D3, which is abolished by expression of cyclin D3T283A, a non-phosphorylatable mutant. Clinically, the expression of cyclin D3 is inversely correlated with the expression of Fbxl8 in lymphomas from human patients implicating Fbxl8 functions as a tumor suppressor.
Keyphrases
- cell cycle
- cell proliferation
- poor prognosis
- endothelial cells
- cell cycle arrest
- bone marrow
- end stage renal disease
- transcription factor
- diffuse large b cell lymphoma
- chronic kidney disease
- newly diagnosed
- binding protein
- squamous cell carcinoma
- pi k akt
- signaling pathway
- oxidative stress
- young adults
- diabetic rats
- protein protein
- squamous cell