Dual regulation of p53 by the ribosome maturation factor SBDS

Qian Hao,Yajie Chen,Shanshan Wang,Jieqiong Wang,Mingming Cao,Hua Lu,Xiang Zhou

doi:10.1038/s41419-020-2393-4

Abstract

The Shwachman-Bodian Diamond syndrome (SBDS)-associated gene, SBDS, is involved in rRNA synthesis and ribosome maturation, but the role of SBDS in cancer is largely elusive. In this study, we found that SBDS is often overexpressed or amplified in human cancers, and high level of endogenous SBDS is significantly associated with unfavorable prognosis. Conversely, knockdown of SBDS leads to p53 stabilization and activation through the ribosomal stress-RPL5/RPL11-MDM2 pathway, resulting in the repression of cancer cell proliferation and invasion. Interestingly, ectopic SBDS in the nucleoplasm also suppresses tumor cell growth and proliferation in vitro and in vivo. Mechanistically, ectopically expressed SBDS triggered by, for example, ribosomal stress binds to the transactivation domain of p53 and perturbs the MDM2–p53 interaction, consequently leading to impaired p53 ubiquitination and proteasomal degradation. Altogether, our finding for the first time demonstrates the dual functions of SBDS in cancer development by coordinating ribosome biogenesis and p53 activity.

Highlights

SBDS was designated because its mutation is highly associated with Shwachman-Diamond syndrome (SDS) or Shwachman-Bodian Diamond syndrome (SBDS) characterized with pancreatic dysfunction, hematologic failure, skeletal abnormalities, and neurological phenotypes[1,2]
SBDS is upregulated in human cancers and associated with unfavorable prognosis Ribosomophathies are frequently accompanied by increased predisposition for cancers, such as acute myeloid leukemia, lymphoma, osteosarcoma, head and neck cancer, and others[3]
These two isogenic cell lines displayed similar colony-forming ability by knocking down SBDS (Fig. S3). This result along with a previous study[8] suggests that persistent depletion of SBDS may lead to translation insufficiency and growth inhibition, regardless of p53 expression, in cancer cells. These findings demonstrate that ablation of endogenous SBDS suppresses cancer cell proliferation and invasion partially through the RPMDM2–p53 signaling pathway, but its long-term deficiency is more detrimental to cell survival owing to its essential role in ribosome biogenesis

Summary

Introduction

SBDS was designated because its mutation is highly associated with Shwachman-Diamond syndrome (SDS) or Shwachman-Bodian Diamond syndrome (SBDS) characterized with pancreatic dysfunction, hematologic failure, skeletal abnormalities, and neurological phenotypes[1,2]. SDS is considered as a type of ribosomopathies, as the SBDS protein is involved in rRNA processing and assembly of the mature 80 S ribosome[3]. Several genetic models have been generated to elucidate the essential role of SBDS during embryonic development[4]. The mice with pancreatic-specific depletion of SBDS manifested the SDS-associated pancreatic insufficiency[7]. This is probably because ablation of SBDS in the regulates p53 activity, during the development of cancer

Methods

Results

Conclusion