Hepatic ribosomal protein S6 (Rps6) insufficiency results in failed bile duct development and loss of hepatocyte viability; a ribosomopathy-like phenotype that is partially p53-dependent

Abstract

Defective ribosome biogenesis (RiBi) underlies a group of clinically diverse human diseases collectively known as the ribosomopathies, core manifestations of which include cytopenias and developmental abnormalities that are believed to stem primarily from an inability to synthesize adequate numbers of ribosomes and concomitant activation of p53. The importance of a correctly functioning RiBi machinery for maintaining tissue homeostasis is illustrated by the observation that, despite having a paucity of certain cell types in early life, ribosomopathy patients have an increased risk for developing cancer later in life. This suggests that hypoproliferative states trigger adaptive responses that can, over time, become maladaptive and inadvertently drive unchecked hyperproliferation and predispose to cancer. Here we describe an experimentally induced ribosomopathy in the mouse and show that a normal level of hepatic ribosomal protein S6 (Rps6) is required for proper bile duct development and preservation of hepatocyte viability and that its insufficiency later promotes overgrowth and predisposes to liver cancer which is accelerated in the absence of the tumor-suppressor PTEN. We also show that the overexpression of c-Myc in the liver ameliorates, while expression of a mutant hyperstable form of p53 partially recapitulates specific aspects of the hepatopathies induced by Rps6 deletion. Surprisingly, co-deletion of p53 in the Rps6-deficient background fails to restore biliary development or significantly improve hepatic function. This study not only reveals a previously unappreciated dependence of the developing liver on adequate levels of Rps6 and exquisitely controlled p53 signaling, but suggests that the increased cancer risk in ribosomopathy patients may, in part, stem from an inability to preserve normal tissue homeostasis in the face of chronic injury and regeneration.

Disrupting Poly(ADP-ribosyl)ating Pathway Creates Premalignant Conditions in Mammalian Liver

“…This type of clonal regenerative nodes rescuing liver function also occurs in several other knockout genetic models [52,59]. It was shown that this surviving tissue represents the clonal expansion of mutated hepatocytes that managed to evade recombination and restore the initial levels of the targeted protein, however, other compensatory mechanism could also be involved [52,59]. We demonstrate that PARG-targeted recombination happened in these nodes.…”

“…These hepatocytes do not display the hypertrophic phenotype, instead, they divide and eventually replace the entire liver tissue. This type of clonal regenerative nodes rescuing liver function also occurs in several other knockout genetic models [52,59]. It was shown that this surviving tissue represents the clonal expansion of mutated hepatocytes that managed to evade recombination and restore the initial levels of the targeted protein, however, other compensatory mechanism could also be involved [52,59].…”

The Effects of Deregulated Ribosomal Biogenesis in Cancer

“…Mdm2 gene amplification is the main mechanism of oncogenic activation [104]. MYC induction enhances the RiBi and stability of the p53 protein, while MYC silencing reduces the expression of RPL5, RPL11, and 5S rRNA in IRBC complexes [105], resulting in a rapid decrease in the p53 protein half-life in a human double minute 2 (HDM2)-dependent manner [106]. RPL5 and RPL11 inhibit MYC transcription and destroy the stability of MYC mRNA, forming a negative feedback loop [104,107].…”

Large language models completely understand molecular characteristics of squamous cervical cancer

“…The major pathway that RPS6 involved in is the PI3K/Akt/mTOR pathway, in which RPS6 interacts with and activates mTOR to promote protein synthesis and cell growth 20 . Alternatively, RPS6 could also inhibit the tumor suppressive function of TP53 to increased risk of tumorigenesis 44 (Figure 3E). Taken together, the superiority of ChatGPT in literature searching and logic presentation liberates human scientists from time-consuming and tedious document work.…”