Fam83F induces p53 stabilisation and promotes its activity

Abstract

p53 is one of the most important tumour suppressor proteins currently known. It is activated in response to DNA damage and this activation leads to proliferation arrest and cell death. The abundance and activity of p53 are tightly controlled and reductions in p53's activity can contribute to the development of cancer. Here, we show that Fam83F increases p53 protein levels by protein stabilisation. Fam83F interacts with p53 and decreases its ubiquitination and degradation. Overexpression of Fam83F also increases p53 activity in cell culture experiments and in zebrafish embryos. Downregulation of Fam83F increases cell proliferation in zebrafish xenografts. Fam83F expression is induced in response to DNA damage. Its downregulation decreases transcription of p53's target genes during the DNA damage response and increases cell proliferation and the colony forming ability of cells, identifying Fam83F as an important regulator of the DNA damage response. Fam83F also enhances migration of cells harbouring mutant p53 demonstrating that it can also activate mutant forms of p53.

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

“…FAM83F has been implicated in oncogenesis with high FAM83F expression observed in oesophageal squamous cell carcinoma (33), lung adenocarcinoma (34), glioma (35) and thyroid carcinoma (36). In contrast, FAM83F has been reported to enhance the stabilisation and activity of the tumour suppressor p53 with siRNA targeting FAM83F reducing cellular proliferation (37). These effects are dependent on the mutational status of p53 with overexpression of FAM83F increasing cell migration in cells containing mutant p53, indicating FAM83F may promote or inhibit cancer progression depending on the tumour's mutational status.…”

FAM83F regulates canonical Wnt signalling through an interaction with CK1α

“…We show here that overexpression of FAM83F protein in cells increases both basal and ligand-dependent canonical Wnt signalling which may explain the reported increase in cell proliferation. FAM83F has also been implicated in the stabilisation of p53 protein, a crucial tumour suppressor, by decreasing p53 ubiquitination and degradation ( 33 ). This stabilisation is also apparent with mutant p53 protein, thus FAM83F may have a tumour suppressor or an oncogenic role depending on the p53 mutational status of the cell ( 33 ).…”

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

“…FAM83F has been implicated in oncogenesis with high FAM83F expression observed in oesophageal squamous cell carcinoma ( Mao et al, 2016 ), lung adenocarcinoma ( Fan et al, 2019 ), glioma ( Xu et al, 2018 ), and thyroid carcinoma ( Fuziwara et al, 2019 ). In contrast, FAM83F has been reported to enhance the stabilisation and activity of the tumour suppressor p53 with siRNA targeting FAM83F reducing cellular proliferation ( Salama et al, 2019 ). These effects are dependent on the mutational status of p53 with overexpression of FAM83F increasing cell migration in cells containing mutant p53, indicating FAM83F may promote or inhibit cancer progression depending on the tumour’s mutational status.…”