Nucleolus-derived mediators in oncogenic stress response and activation of p53-dependent pathways

Abstract

Rapid growth and division of cells, including tumor ones, is correlated with intensive protein biosynthesis. The output of nucleoli, organelles where translational machineries are formed, depends on a rate of particular stages of ribosome production and on accessibility of elements crucial for their effective functioning, including substrates, enzymes as well as energy resources. Different factors that induce cellular stress also often lead to nucleolar dysfunction which results in ribosome biogenesis impairment. Such nucleolar disorders, called nucleolar or ribosomal stress, usually affect cellular functioning which in fact is a result of p53-dependent pathway activation, elicited as a response to stress. These pathways direct cells to new destinations such as cell cycle arrest, damage repair, differentiation, autophagy, programmed cell death or aging. In the case of impaired nucleolar functioning, nucleolar and ribosomal proteins mediate activation of the p53 pathways. They are also triggered as a response to oncogenic factor overexpression to protect tissues and organs against extensive proliferation of abnormal cells. Intentional impairment of any step of ribosome biosynthesis which would direct the cells to these destinations could be a strategy used in anticancer therapy. This review presents current knowledge on a nucleolus, mainly in relation to cancer biology, which is an important and extremely sensitive element of the mechanism participating in cellular stress reaction mediating activation of the p53 pathways in order to counteract stress effects, especially cancer development.

Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

“…Recently, an increasing number of studies have demonstrated the essential regulatory roles of ribosomal proteins in many ribosome-independent cellular processes. The best-known case is the nucleolar stressinduced p53 activation (15,18,41,42). Under cellular stresses, including nutrition depletion and DNA damage stimuli, ribosomal proteins, such as RPL5, RPL6, and RPL11, translocate from the nucleoli to the nucleoplasm, where they bind to HDM2, stabilizing p53 (9).…”

“…Knockdown of RPS26 greatly reduces the recruitment of p53 to the promoters of its target genes and inhibits p53 acetylation. It has been found that mutations in r-protein genes, including those for RPL22, RPL10, RPL5, and RPL11, lead to the dysfunction of ribosome biogenesis in cancers (17,18). However, other ribosome-independent functions of r-proteins remain to be elucidated.…”

In Focus in HCB

“…Other established functions of the nucleolus include the assembly of signal recognition particles, modification of transfer RNAs and sensing cellular stress. In this issue, a review by Stępiński (2016) provides an overview of the functional involvement of the nucleolus in sensing and responding to various forms of cellular stress. The nucleolar involvement in stress response leads to inhibition of ribosome biogenesis, called nucleolar/ribosomal stress, which is associated with the disruption of the nucleolar structure.…”

The nucleolus, an ally, and an enemy of cancer cells

“…There are many well-known synthetic and natural drugs targeting nucleolar functions which are used to combat cancer cells (Quin et al 2014; Stępiński 2016; Woods et al 2015). Interestingly, proteomic analyses revealed that upon exposure to nucleolar stress-eliciting antitumor drugs, regardless of the fact whether they originate from plants as TBMS1 (saponin from Bolbostemma paniculatum ) (Lin et al 2016b) or are obtained by chemical synthesis as oxaliplatin (Ozdian et al 2017), proteins in cancer cells, including RPs, exhibit different expression, some are upregulated, and the others are downregulated.…”