Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch

Abstract

The tumor suppressor Fbxw7 (also known as Sel-10, hCdc4, hAgo, or Fbw7) is an F-box protein that functions as the substrate-recognition subunit of an SCF ubiquitin ligase complex and targets a group of oncoproteins for degradation. We now show that Fbxw7 regulates the proliferation and differentiation of keratinocytes by mediating the degradation of c-Myc and Notch proteins. Fbxw7-deficient keratinocytes showed an increased proliferative capacity that was dependent on the accumulation of c-Myc but not on that of Notch. Fbxw7 deficiency also resulted in the premature differentiation of keratinocytes in a manner dependent on both c-Myc and Notch. Although Fbxw7-deficient keratinocytes proliferated excessively in vitro, loss of Fbxw7 did not predispose keratinocytes to the formation of squamous cell carcinoma in vivo induced by the expression of oncogenic Ras, possibly because the stem cell population of keratinocytes becomes exhausted as a result of enhanced Notch activity. Indeed, suppression of Notch signaling by additional ablation of RBP-J in Fbxw7-deficient keratinocytes conferred a more aggressive tumorigenic capacity. Collectively, these results indicate that Fbxw7 controls the proliferation and differentiation of keratinocytes, and that it exerts both inhibitory and stimulatory actions in skin carcinogenesis by counteracting the proliferation-promoting effect of c-Myc and the tumor-suppressive effect of Notch, respectively.

Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15

“…The half-life of c-Myc in keratinocytes is regulated by the E3 ligases Fbxw7 (Ishikawa et al 2013) and Skp2 (Muller and Eilers 2008). For Fbxw7-mediated c-Myc degradation to occur, c-Myc must be phosphorylated on Thr 58 by ERK and on Ser 62 by GSKb (Muller and Eilers 2008).…”

Cellular senescence and protein degradation

“…However, this more complex picture does not exclude the possibility that some E3 ligases could play a more critical role in the senescent phenotype. Indeed, as discussed previously, SCF-FBW7 is a well-known tumor suppressor and has been recently shown to contribute to senescence, 243,247,256 and correspondingly many FBW7 targets are degraded in SAPD. The CUL4A-DDB1 (SCF4) complex and its interacting receptor protein DDB2 are also strong candidates, since both have been shown to drive senescence.…”

E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma

“…FBW7 mutants cannot bind to the NICD. Although the mutant forms of FBW7 were still able to bind to Myc, they do not target it for degradation [29,33]. In melanoma Notch expression is increased.…”

“…Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis [29,30,32,33]. FBW7 mutation rates in cholangiocarcinoma, T-cell acute lymphocytic leukemia, endometrial carcinoma, and colorectal cancer were reported as 35%, 31%, 9%, and 9%, respectively [29,30,34].…”

“…Interestingly, presenilin, one of the components of the g-secretase complex was found to regulate the ubiquitin ligase FBW7 to modulate EGFR signaling and cell transformation [36]. FBW7 mutations in leukemic cells mediate Notch pathway activation and resistance to g-secretase inhibitors [33]. FBW7 mutants cannot bind to the NICD.…”