GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins

Abstract

Increasing attention has been paid to certain ribosomal or ribosome biosynthesis-related proteins involved in oncogenesis. Members of one group are classified as "tumor suppressive factors" represented by RPL5 and RPL11; loss of their functions leads to cancer predisposition. RPL5 and RPL11 prevent tumorigenesis by binding to and inhibiting the MDM2 ubiquitin ligase and thereby up-regulating p53. Many other candidate tumor suppressive ribosomal/nucleolar proteins have been suggested. However, it remains to be experimentally clarified whether many of these factors can actually prevent tumorigenesis and if so, how they do so. Conversely, some ribosomal/nucleolar proteins promote tumorigenesis. For example, PICT1 binds to and anchors RPL11 in nucleoli, down-regulating p53 and promoting tumorigenesis. GRWD1 was recently identified as another such factor. When overexpressed, GRWD1 suppresses p53 and transforms normal human cells, probably by binding to RPL11 and sequestrating it from MDM2. However, other pathways may also be involved.

Keywords: GRWD1; PICT1; RPL11; nucleolar stress response; oncogene; p53; tumor suppressor.

Figure 1.

A model for p53 regulation by ribosomal/nucleolar proteins. (A) In unstressed cells, tumor suppressive ribosomal proteins (RPs) such as RPL11 localize in the nucleolus, and MDM2 binds to and ubiquitinates p53. As a result, the cellular p53 level is kept low. (B) Nucleolar stress disrupts the nucleolus and releases the RPs into the nucleoplasm, where they interact with MDM2 and inhibit its ubiquitin ligase activity, inducing p53. (C) Other stresses such as DNA double-strand breaks and hypergrowth stimuli (e.g., expression of activated RAS) are also suggested to induce release of the RPs into the nucleoplasm, contributing to p53 induction. It is unclear whether nucleolar breakdown occurs under such conditions. (D) In cancer-prone ribosomopathy cells, the levels of the RPs are decreased by heterozygous mutations (or homozygous mutations for some factors). As a result, the RP-MDM2-p53 pathway cannot function in stressed cells, leading to tumorigenesis. (E) When overexpressed, GRWD1 binds to and inhibits RPL11, thereby down-regulating p53. As a result, tumor formation is promoted. As detailed in the text, PICT1 similarly binds to RPL11 and thereby inhibits p53.