Ribosomal Proteins and Human Diseases: Pathogenesis, Molecular Mechanisms, and Therapeutic Implications

Abstract

Ribosomes are essential components of the protein synthesis machinery. The process of ribosome biogenesis is well organized and tightly regulated. Recent studies have shown that ribosomal proteins (RPs) have extraribosomal functions that are involved in cell proliferation, differentiation, apoptosis, DNA repair, and other cellular processes. The dysfunction of RPs has been linked to the development and progression of hematological, metabolic, and cardiovascular diseases and cancer. Perturbation of ribosome biogenesis results in ribosomal stress, which triggers activation of the p53 signaling pathway through RPs-MDM2 interactions, resulting in p53-dependent cell cycle arrest and apoptosis. RPs also regulate cellular functions through p53-independent mechanisms. We herein review the recent advances in several forefronts of RP research, including the understanding of their biological features and roles in regulating cellular functions, maintaining cell homeostasis, and their involvement in the pathogenesis of human diseases. We also highlight the translational potential of this research for the identification of molecular biomarkers, and in the discovery and development of novel treatments for human diseases.

The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity

“…Furthermore, patients with two human congenital disorders, Diamond-Blackfan anemia (DBA) and 5q-syndrome, both of which are characterized by deletions or mutations in multiple RP genes, are at higher risk of developing cancers. Taken together, these data strongly suggest a close association of dysfunction of RPs with human tumorigenesis (for recent comprehensive reviews, see (de las Heras-Rubio et al, 2014;Kim et al, 2014;Wang et al, 2015a;Zhou et al, 2012)). In this review, we will focus on the roles of RPs in regulation of cell growth, tumorigenesis and genome integrity, and discuss RPs as potential cancer biomarkers for early diagnosis and prognosis.…”

“…As suggested by Warner and McIntosh (Warner and McIntosh, 2009), the following criteria must be met to define extraribosomal functions of RPs: (i) interaction with some nonribosomal components of the cell; (ii) the interaction has physiological effects on cellular functions; (iii) the effects occur away from ribosomes; (iv) the effects do not influence protein synthesis. This section will mainly focus on extraribosomal functions of RPs related to a few key cellular processes whose abnormal regulation would lead to tumorigenesis, including apoptosis, cell cycle arrest, cell proliferation, neoplastic transformation, and cell migration and invasion (de las Heras-Rubio et al, 2014;Takada and Kurisaki, 2015;Wang et al, 2015a) (Table 1).…”

Piper longum: A review of its phytochemicals and their network pharmacological evaluation

“…Extraribosomal function of ribosomal proteins include regulation of gene expression, cell-cycle control, regulation of apoptosis, modulation of DNA repair, regulation of development and differentiation, modulation of cell migration and invasion and regulation of angiogenesis (Wang et al, 2015). Dysfunction of ribosome leads to a condition known as ribosomopathies.…”

Full Issue

“…High expression of chordin and noggin-1 were detected in early cleavage stage embryos, right after fertilization, indicating maternally packaged chordin and noggin-1 may have unique function in early embryonic development in A. limnaeus (Wagner and Podrabsky 2015). Another study revealed three BMP genes in zebrafish (zBMPs) embryos, BMP-2a, BMP-2b and BMP-4, were expressed in 4, 8,11, and 36 hours after fertilization (Martinez -Barbera, 1997). Human, mouse, Xenopus, and zebrafish BMP-2 and BMP-4 share a conserved sequence motif .…”