Nucleolar protein GLTSCR2 stabilizes p53 in response to ribosomal stresses

Abstract

p53 is a key regulator of cell growth and death by controlling cell cycle progression and apoptosis under conditions of stress such as DNA damage or oncogenic stimulation. As these processes are critical for cell function and inhibition of tumor development, p53 regulatory pathways are strictly monitored in cells. Recently, it was recognized that nucleolar proteins, including nucleophosmin/B23, ribosomal protein L11, and alternate reading frame (ARF), form the nucleolus-ARF-murine double minute 2 (MDM2) axis in p53 regulatory pathways, which increases p53 stability by suppressing the activity of MDM2. In this work, we show that nucleolar protein glioma tumor-suppressor candidate region gene 2 (GLTSCR2) translocates to the nucleoplasm under ribosomal stress, where it interacts with and stabilizes p53 and inhibits cell cycle progression without the involvement of the major upstream p53 regulator, ARF. Furthermore, ectopic expression of GLTSCR2 significantly suppressed growth of cancer cells in a xenograft animal model via p53-dependent pathway. Our data identify GLTSCR2 as a new member of the nucleolus-nucleoplasmic axis for p53 regulation. ARF-independent direct regulation of p53 by GLTSCR2 may be a key mechanism and therapeutic target for cell death or growth inhibition when nucleolus-ARF-p53 pathways are inactivated by genetic or epigenetic modifications of ARF, which are the second most common types of genetic change observed in human cancers.

GLTSCR2/PICT1 links mitochondrial stress and Myc signaling

“…The induction of Myc in conditions of mitochondrial stress may serve an adaptive function of stimulating glucose uptake and glycolysis to compensate for the impairment of oxidative phosphorylation, while also attempting to restore mitochondrial activity. Previous studies have suggested that GLTSCR2 is induced by genotoxic stressors, such as ionizing radiation and UV radiation, and low-dose actinomycin D, which is thought to cause ribosomal stress by inhibiting rRNA synthesis (28,29). It is possible that some of these agents may also impinge upon mitochondrial function and activate pathways leading to the induction of GLTSCR2.…”

Molecular dynamics of the full-length p53 monomer

“…37 This results in significant changes in its functional properties as a transcription factor. [38][39][40][41][42][43] As a consequence of the p53 isoforms function as a transcription factor and its involvement in DNA damage, it is evident that the status of p53 plays a crucial role in cancer progression [44][45][46][47][48][49][50][51][52] as well in different physiological 2 and anticancer responses. 42 In fact, p53 is frequently mutated in cancer, resulting in novel "gain-of-function"effects.…”

Transcriptome profile analysis reveals specific signatures of pollutants in Atlantic eels

“…Interestingly, the transcription level of these genes was found to increase or decrease with increasing fish HSI. This could be linked, at least in part, to the fact that these genes are not only involved in protein translation but also in cell cycle by regulating the accumulation of the p53 protein in cell (Horn and Vousden 2008;Lee et al 2012). The p53 protein is involved in cell cycle arrest and apoptosis.…”