Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3

Abstract

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.

CircMYLK promotes the growth, migration, invasion, and survival of bladder cancer cells by upregulating CCND3 level via competitively binding to miR‐34a

“…CCND3 amplification was previously shown to be a marker of aggressive bladder cancer (Beltran et al, 2013), and CCND3 was also supported as urine biomarker of bladder cancer recurrence (Blanca et al, 2016). Besides, CCND3 promoted tumorigenesis and development of numerous other types of cancers (Yoshida et al, 2021;Yu et al, 2018), suggesting that CCDN3 was a wide oncogene in various cancers. Importantly, we found that cir-cMYLK could decoy miR-34a and thus increasing the expression level of CCND3.…”

Ubiquitylation of unphosphorylated c-myc by novel E3 ligase SCFFbxl8

“…As a positive control, we assessed coprecipitation of cyclin D3 since we have already established cyclin D3 as a direct Fbxl8 substrate. 10 Both c-myc and cyclin D3 were detected in Fbxl8 precipitates ( Figure 1(b )). To address binding specificity, we assessed the ability of c-myc to bind to a panel of Fbxl8 deletion mutants.…”

“… 14 Fbxl8 knockdown also accelerates G1 to S-phase entry in mammalian cells. 10 Therefore, it was critical to investigate the status of c-myc protein levels in this cell cycle-specific context. We obtained conditional knockout mice generated by Cyagen, wherein exon 3 (which encodes the F-box domain) of the Fbxl8 gene is flanked by LoxP sequences ( Figure 5(a )).…”

The Long-Lost Ligase: CRL4AMBRA1 Regulates the Stability of D-Type Cyclins

“…A family of F-box proteins (69 in human) serves as the substrate receptors of SCFs. Multiple F-box proteins have been reported to target cyclin D1 (reviewed by Qie and Diehl, 2020), and distinct F-box proteins have been linked to cyclin D2 and cyclin D3 (Chen et al, 2012a , 2012b; Yoshida et al , 2021 ). Still other studies have implicated the anaphase promoting complex/cyclosome (APC/C) in cyclin D1 ubiquitylation (Agami and Bernards, 2000 ; Pawar et al , 2010 ).…”