Fbxw7 Tumor Suppressor

Abstract

Rapidly accumulating data indicate that F-box/WD repeat-containing protein 7 (Fbxw7) is one of the most frequently mutated genes in human cancers and regulates a network of crucial oncoproteins. These studies have generated important new insights into tumorigenesis and may soon enable therapies targeting the Fbxw7 pathway.We searched PubMed, Embase, and ISI Web of Science databases (1973–2015, especially recent 5 years) for articles published in the English language using the key words “Fbxw7,” “Fbw7,” “hCDC4,” and “Sel-10,” and we reviewed recent developments in the search for Fbxw7.Fbxw7 coordinates the ubiquitin-dependent proteolysis of several critical cellular regulators, thereby controlling essential processes, such as cell cycle, differentiation, and apoptosis. Fbxw7 contains 3 isoforms (Fbxw7α, Fbxw7β, and Fbxw7γ), and they are differently regulated in subtract recognition. Besides those, Fbxw7 activity is controlled at different levels, resulting in specific and tunable regulation of the abundance and activity of its substrates in a variety of human solid tumor types, including glioma malignancy, nasopharyngeal carcinoma, osteosarcoma, melanoma as well as colorectal, lung, breast, gastric, liver, pancreatic, renal, prostate, endometrial, and esophageal cancers.Fbxw7 is strongly associated with tumorigenesis, and the mechanisms and consequences of Fbxw7 deregulation in cancers may soon enable the development of novel therapeutic approaches.

Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses

“…FBXW7 mutations are uncommon in lung cancer, according to COSMIC. FBXW7 is implicated in proteasome degradation of specific substrates and control tumorigenesis, acting on cell cycle, differentiation and apoptosis [37]. It is also involved in epithelial-to-mesenchymal transition by controlling mTOR pathway [38].…”

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

“…The FBXW7 gene, which encodes FBW7, is frequently mutated in diverse cancer types including leukemia and breast, colon, liver, ovarian, and lung cancers [26][27][28] . FBW7 expression is transcriptionally regulated by the tumor suppressor p53 29 , and loss-of-function of p53 reduces the expression of FBW7 30 . Therefore, the tumor-suppressive function of FBW7 may be considered only in the context of p53.…”

FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

“…With a mutation rate of 6% to 35%, it is considered to be the most common tumor suppressor right behind p53 and PTEN 7. In addition, many upstream molecules, such as transcriptional factors, kinases and microRNA, can also regulate FBW7 either transcriptionally or post‐translationally 24.…”

“…Cell proliferation is tightly associated with the cell cycle, which is rigidly regulated by a series of kinases, among which Cyclin E and Aurora B are 2 important FBW7 substrates involved in the promotion of G1/S and G2/M transition, respectively 5, 8, 21. Previous studies have implicated the role of FBW7 in the regulation of cell proliferation in colon, breast and kidney cancers 7. In our study, we found that forced FBW7 expression inhibited the proliferation of glioma cells.…”

“…It is an important tumor suppressor with dominant‐negative mutations in a multitude of tumors, including gastric, colorectal, breast, pancreatic, liver, prostate and endometrial cancers, as well as leukemia and osteosarcoma 5, 7. To date, multiple substrates of FBW7 have been identified, which include a series of important oncoproteins like Cyclin E, c‐Myc, Jun, Mcl1 and Sox9 that are involved in the regulation of cell division, apoptosis, differentiation and some classical oncogenic signaling pathways, such as Notch and mTOR 8, 9, 10, 11, 12, 13, 14.…”