Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells

Abstract

Constitutive expression of active Akt (Akttg) drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal protein S6 (rpS6), an Akt effector, we generated mice that express constitutive Akt in β-cells in the background of unphosphorylatable ribosomal protein S6 (rpS6P-/-). rpS6 phosphorylation deficiency failed to block Akttg-induced hypertrophy and aneuploidy in β-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation. In contrast, rpS6 phosphorylation deficiency efficiently restrained the reduction in nuclear localization of the cell cycle inhibitor p27, as well as the development of Akttg-driven hyperplasia and tumor formation in β-cells. In vitro experiments with Akttg and rpS6P-/-;Akttg fibroblasts demonstrated that rpS6 phosphorylation deficiency leads to reduced translation fidelity, which might underlie its anti-tumorigenic effect in the pancreas. However, the role of translation infidelity in tumor suppression cannot simply be inferred from this heterologous experimental model, as rpS6 phosphorylation deficiency unexpectedly elevated the resistance of Akttg fibroblasts to proteotoxic, genotoxic as well as autophagic stresses. In contrast, rpS6P-/- fibroblasts exhibited a higher sensitivity to these stresses upon constitutive expression of oncogenic Kras. The latter result provides a possible mechanistic explanation for the ability of rpS6 phosphorylation deficiency to enhance DNA damage and protect mice from Kras-induced neoplastic transformation in the exocrine pancreas. We propose that Akt1 and Kras exert their oncogenic properties through distinct mechanisms, even though both show addiction to rpS6 phosphorylation.

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

“…Conversely, ectopic expression of a constitutively active form of AKT (Myr-AKT) (Fulton et al, 1999;Sun et al, 2014), while increasing phospho-S6 levels as expected (Wittenberg et al, 2016), did not increase PDHK1 levels in PTEN-expressing cells ( Figure 3C).…”

Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection

“…RPS6 phosphorylation is largely regulated by the activity of two kinases: p70 S6 kinase (P70S6K) and p90 RSK kinase (P90S6K), both of which phosphorylate RPS6 on Ser235/236. RPS6 phosphorylation has been linked to cell size and proliferation (Pende et al, 2000; Ruvinsky et al, 2005), clearance of apoptotic cells (Jeon et al, 2008), and protection against DNA damage in cancerous cells (Khalaileh et al, 2013; Wittenberg et al, 2016). RPS6 has also been linked to regulation of free amino-acid levels (Ruvinsky and Meyuhas, 2006), glucose homeostasis (Pende et al, 2000; Ruvinsky et al, 2005), and lipid biosynthesis (Calvisi et al, 2011), all of which are important for parasite growth (Itani et al, 2014; Itoe et al, 2014; Meireles et al, 2017).…”

Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells

“…Notably, p-S6 itself, besides Akt, has also been implicated in cell survival [36][37][38]. MEFs with phospho-defective/unphosphorylatable S6 (S6 P−/− ) were more sensitive to apoptotic inducers than wild-type MEFs [37,38]. This might explain our observation that SAL-induced cellular senescent cells exhibit resistance to MK2206.…”

“…Thus, we suggest that SAL treatment bypassed Akt and phosphorylated directly or indirectly S6. The p-S6 itself has also been implicated with cell survival [36][37][38]. The S6 P−/− mediates sensitivity to TRAIL-, etoposide-, or MG132-induced apoptosis in MEFs [37,38], thus suggesting that p-S6 is a critical pro-survival factor.…”

“…Hence, the data also indicate that the p-S6 level might be regulated in part by AR ligand, independent of Aktphosphorylation. Notably, p-S6 itself, besides Akt, has also been implicated in cell survival [36][37][38]. MEFs with phospho-defective/unphosphorylatable S6 (S6 P−/− ) were more sensitive to apoptotic inducers than wild-type MEFs [37,38].…”