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Project description:A Germline Point Mutation in the MYC-FBW7 Phosphodegron Results in a Tumor-Prone Phenotype
| PRJNA1040270 | ENA
Project description:c-Myc (hereafter, Myc) is a cancer driver whose abundance is regulated by the SCFFbw7 ubiquitin ligase and proteasomal degradation. Fbw7 binds to a phosphorylated Myc degron centered at threonine 58 (T58), and mutations of Fbw7 or T58 impair Myc degradation in cancers. Here, we identify a second Fbw7 phosphodegron at Myc T244 that is required for Myc ubiquitylation and acts in concert with T58 to engage Fbw7. While Ras-dependent Myc serine 62 phosphorylation (pS62) is thought to stabilize Myc by preventing Fbw7 binding, we find instead that pS62 greatly enhances Fbw7 binding and is an integral part of a high-affinity degron. Crystallographic studies revealed that both degrons bind Fbw7 in their diphosphorylated forms and that the T244 degron is recognized via a unique mode involving Fbw7 arginine 689 (R689), a mutational hotspot in cancers. These insights have important implications for Myc-associated tumorigenesis and therapeutic strategies targeting Myc stability.
| S-EPMC8797792 | biostudies-literature
Project description:Myc proteins regulate cell growth and division and are implicated in a wide range of human cancers. We show here that Fbw7, a component of the SCF(Fbw7) ubiquitin ligase and a tumor suppressor, promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro. Phosphorylation of c-Myc on threonine-58 (T58) by glycogen synthase kinase 3 regulates the binding of Fbw7 to c-Myc as well as Fbw7-mediated c-Myc degradation and ubiquitination. T58 is the most frequent site of c-myc mutations in lymphoma cells, and our findings suggest that c-Myc activation is one of the key oncogenic consequences of Fbw7 loss in cancer. Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis.
| S-EPMC428477 | biostudies-literature
Project description:DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2-/-). Consistent with the human disease (XP-E), the DDB2-/- mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.
| S-EPMC2892891 | biostudies-literature
Project description:CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype.All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced.Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010).Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.
| S-EPMC3607098 | biostudies-literature
Project description:We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases.
| S-EPMC2363618 | biostudies-other
Project description:Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. Long chain acyl-CoA synthetase 4 (ACSL4), an enzyme has pivotal roles in arachidonic acid (AA) metabolism. However, its function and the underlying molecular mechanisms in HCC are still not fully elucidated. Here, we identified ACSL4 as a novel marker for AFP high subtype HCC through transcriptome profiling. ACSL4 was frequently upregulated in HCC samples and associated with poor prognosis. Functionally, ACSL4 knockdown resulted in decreased cell growth, whereas ectopic ACSL4 expression facilitated tumor formation in vitro and in vivo. Mechanistically, ACSL4 stabilized the oncoprotein c-Myc through ubiquitin-proteasome system in an ERK/FBW7-dependent manner. Cell growth ability mediated by ACSL4 elevation was partly attenuated by c-Myc depletion using siRNA or its inhibitor 10058-F4. In contrast, the effects of ACSL4 silencing were partially reversed by c-Myc overexpression via FBW7 knockdown. Clinically, ACSL4 expression was positively correlated with c-Myc in HCC. In conclusion, ACSL4 is a novel marker for AFP high subtype HCC. Our data uncovered a new mechanism by which ACSL4 promotes HCC progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis and could be a valuable prognostic biomarker and a potential therapeutic target in HCC.
| S-EPMC7190855 | biostudies-literature
Project description:Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.
| S-EPMC7857045 | biostudies-literature
Project description:In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in 'ultramutated' sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.
| S-EPMC5243902 | biostudies-literature
Project description:Definitive hematopoiesis requires the master hematopoietic transcription factor Runx1, which is a frequent target of leukemia-related chromosomal translocations. Several of the translocation-generated fusion proteins retain the DNA binding activity of Runx1, but lose subnuclear targeting and associated transactivation potential. Complete loss of these functions in vivo resembles Runx1 ablation, which causes embryonic lethality. We developed a knock-in mouse that expresses full-length Runx1 with a mutation in the subnuclear targeting cofactor interaction domain, Runx1(HTY350-352AAA). Mutant mice survive to adulthood, and hematopoietic stem cell emergence appears to be unaltered. However, defects are observed in multiple differentiated hematopoietic lineages at stages where Runx1 is known to play key roles. Thus, a germline mutation in Runx1 reveals uncoupling of its functions during developmental hematopoiesis from subsequent differentiation across multiple hematopoietic lineages in the adult. These findings indicate that subnuclear targeting and cofactor interactions with Runx1 are important in many compartments throughout hematopoietic differentiation.
| S-EPMC3909992 | biostudies-literature