The ribosome is an end product of a regulated complex reaction between proteins and ribosomal RNA and this process begins in the cell nucleolus. It is made up of the 40S and 60S ribosomal subunits and each subunit is an assembly of processed and matured ribosomal proteins and RNAs (18S, 5.8S, 28S, and 5S). A steady-state is maintained within the nucleolus if there is no compromise to the intricate coordination of the complex process of ribosomal synthesis. Therefore, any form of dysregulation to this homeostatic process will trigger nucleolar stress characterized by P53 mediated G1 cell cycle arrest and/or induction of apoptosis.
It is well known that ribosome biogenesis is over-activated in cancer cells, to cope with their hyper-proliferating state. The high level of abnormal synthesis of ribosomes in cancer cells is very sensitive to nucleolar stress. They respond to nucleolar stress (disruption of rRNA synthesis) through activation of P53. In a steady state, P53 is maintained in a reduced state by binding to MDM2(E3 ubiquitin-protein ligase) which mediates its proteolytic degradation. On the other hand, in cancer cells, nucleolar stress is generated through disruption in rRNA synthesis and this, in turn, leads to P53 activation. This is made possible through the inhibitory effect of free ribosomal proteins on MDM2 which is meant to put the level of P53 to check.
Concerning its anti-proliferative effect in response to stress, studies have revealed that P53 triggers a transcriptional process that affects a wide variety of normal biological processes which include metabolism, reactive oxygen species control, and autophagy. This P53 transcription program is tissue and stress-specific. Studies carried out on solid tumors revealed different degrees of sensitivity and more cytostatic effect than apoptotic. The cytostatic effect has been attributed to transcriptional activation of p21 which leads to a G1- cell cycle arrest. Therefore, understanding p53 specific transcriptional response to nucleolar stress is going to be very instrumental in cancer therapy through disruption of ribosome synthesis.
In a new study published in the Journal Molecular Biology of the Cell, University of Texas Health Science Center scientists: Han Liao, Anushri Gaur, Claire Mauvaise, and led by Professor Catherine Denicourt conducted an in-depth gene expression analysis to check for transcripts induced by P53 and they found out that nucleolar stress activates the p53-transcriptional survival program (genes involved in autophagy, metabolism, and ROS control). They inhibited rRNA processing in colon cancer cells by depleting LAS1L needed for 28S rRNA processing and the Synthesis of 60S ribosomal subunit. After five days they noticed a little but significant drop in cell viability and an increased number of cells undergoing autophagy which were likely due to activated p53. Activated P53 was also observed to be a possible cause of cancer cell survival through its activation of transcription of genes involved in the arrest of the cell cycle, metabolism, ROS control, and autophagy. The research team found that upregulation of autophagy genes in response to nucleolar stress depends on p53 and blocking autophagy could be instrumental in disturbing the survival of P53-positive cancer cells after inhibiting ribosome synthesis.
In a nutshell, through this experiment, the authors have demonstrated that inhibition of ribosome synthesis leads to p53- induced activation of the survival transcription process which in turn results in the arrest of the cell cycle, activation of the autophagy pathway in p53 positive cancer cells, and upregulation of genes involved in the regulation of central metabolisms and ROI control. Therefore, blocking the autophagy pathway is suggested to be a treatment strategy in a p53 positive cancer with inhibited ribosome synthesis.
Han Liao, Anushri Gaur, Claire Mauvais, Catherine Denicourt. p53 induces a survival transcriptional response after nucleolar stress. Mol Biol Cell, . 2021;32(20):ar3. doi: 10.1091/mbc.E21-05-0251.