Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF

Abstract

Pituitary tumor-transforming gene 1-binding factor (PTTG1IP; PBF) is a multifunctional glycoprotein, which is overexpressed in a wide range of tumours, and significantly associated with poorer oncological outcomes, such as early tumour recurrence, distant metastasis, extramural vascular invasion and decreased disease-specific survival. PBF transforms NIH 3T3 fibroblasts and induces tumours in nude mice, while mice harbouring transgenic thyroidal PBF expression show hyperplasia and macrofollicular lesions. Our assumption that PBF becomes an oncogene purely through increased expression has been challenged by the recent report of mutations in PBF within the Catalogue of Somatic Mutations in Cancer (COSMIC) database. We therefore sought to determine whether the first 10 PBF missense substitutions in human cancer might be oncogenic. Anisomycin half-life studies revealed that most mutations were associated with reduced protein stability compared to wild-type (WT) PBF. Proliferation assays narrowed our interest to two mutational events which significantly altered cell turnover: C51R and R140W. C51R was mainly confined to the endoplasmic reticulum while R140W was apparent in the Golgi apparatus. Both C51R and R140W lost the capacity to induce cellular migration and significantly reduced cell invasion. Colony formation and soft agar assays demonstrated that, in contrast to WT PBF, both mutants were unable to elicit significant colony formation or anchorage-independent growth. However, C51R and R140W retained the ability to repress radioiodide uptake, a functional hallmark of PBF. Our data reveal new insight into PBF function and confirm that, rather than being oncogenic, mutations in PBF are likely to be passenger effects, with overexpression of PBF the more important aetiological event in human cancer.

Recurrence of Papillary Thyroid Cancer: A Systematic Appraisal of Risk Factors

“…The following day, Corning BioCoat growth factor reduced Matrigel invasion chambers (Corning; New York, USA) were warmed and rehydrated. Initial experiments evaluated optimum cell density for each line (data not shown), and invasion assays were carried out as we have described previously ( 34 ), before Eosin Y solution (Sigma-Aldrich) staining and being photographed on an EVOS XL Core Imaging System (ThermoFisher Scientific).…”

Establishment of an endoplasmic reticulum stress-related signature predicting outcomes of gastric adenocarcinoma patients

“…According to another report, p53 participates in the regulation of mitochondrial and ER interactions, and the knockdown of p53 reduces ER stress-induced injury in mouse cardiomyocytes by protecting mitochondria ( Chen et al, 2019 ). Interestingly, a mutant of PTTG1IP, C51R, was reported to be mainly confined to the endoplasmic reticulum ( Imruetaicharoenchoke et al, 2017 ). PTTG1IP may not be directly related to ER stress, but they may be indirectly involved in ER stress processes due to their close interaction with p53.…”

Hypermethylation of the PTTG1IP promoter leads to low expression in early‑stage non‑small cell lung cancer

“…A number of studies have suggested that the subcellular localization of PTTG1IP and PTTG1 is crucial for progression of mitosis through the metaphase-anaphase transition (14,15,18). PTTG1IP promotes PTTG1 activation by promoting transfer of PTTG1 from the cytoplasm to the nucleus, thereby allowing the interaction between separase and PTTG1 (50).…”

“…Pituitary tumor transforming gene 1 binding factor ( PTTG1IP ; also termed PBF) is a ubiquitously expressed proto-oncogene. PTTG1IP was first identified through its ability to bind to human securin, also termed pituitary tumor transforming gene ( PTTG ) (14,15). Thus far, PTTG1IP has been reported to be highly expressed in thyroid, breast, colorectal, and liver cancer (16–19).…”