One of the hallmarks of neurodegenerative diseases is the accumulation of protein inclusions and translational deficits might account for altered protein homeostasis with a toxic impact on cell functions and survival. Deficits in rRNA synthesis and processing have strong effects on neuronal function and survival, and multiple modalities account for their toxic impact. An imbalance in any of their biosynthetic steps may result in dysfunctional protein synthesis altering cellular homeostasis. It is somehow predictable that deficits in rRNA functions have severe consequences for the cells. Current evidence suggests that rRNA dysfunctions might affect the neurodegenerative process, for example, by highly specific and selective functions within the protein synthesis.
The essential role of increased ribosome biogenesis and protein synthesis in sustaining tumor cell growth and proliferation is well established. However, a number of recent studies suggest that both increased numbers and altered modifications of ribosomes drive tumorigenesis. Hyperactive ribosome biogenesis results in several cellular challenges that can be detrimental to normal cell growth and survival, including increased instability of ribosomal DNA (rDNA) regions and the alteration of energy homeostasis or protein homeostasis, the latter potentially leading to proteotoxic stress. Protective mechanisms that regulate the RNA polymerase I (Pol I)-dependent transcription of rRNA, multiple other steps in ribosome biogenesis, or the catabolism of proteins have evolved to prevent and resolve these cellular challenges. In cancer cells, several of these protective mechanisms are dysregulated, such as hyperactivation of mTOR signaling induced by oncogenic activation of the RAS and PI3K AKT pathways, downregulation of energy-dependent nucleolar silencing complex (eNoSC) components, or dysregulation of the DNA damage response (DDR). Selective pressures allow some cancer cells to convert these challenges into opportunities to gain a more aggressive phenotype. Two main examples of these opportunistic alterations due to increased rates of ribosomal biogenesis and protein synthesis are the induction of the heat shock transcription factor 1 (HSF1)-the dependent transcriptional program that supports a highly malignant phenotype and the induced expression of programmed death-ligand 1 (PDL1) and PDL2, which allow cancer cells to evade T cell-mediated cytotoxicity. However, protective mechanisms, challenges, and opportunities related to hyperactive ribosome biogenesis uncover tumor-cell-specific vulnerabilities that can be exploited therapeutically.
Fig.1 Dysregulated ribosome biogenesis in cancer. (Pelletier, 2018)
Ribosomopathies are inherited or sporadic disorders caused by the haploinsufficiency of genes encoding key factors in ribosome biogenesis or ribosome structural proteins. Such mutations often lead to tissue-specific developmental phenotypes, and the mechanisms underlying such tissue specificity have drawn considerable attention in light of the ubiquitous requirement for ribosomes in all cells. The list of conditions thought to involve or result from ribosomal stress is extensive and varied. Examples include Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome, Treacher Collins syndrome, chromosome 5q syndrome, North American Indian childhood cirrhosis, and isolated congenital asplenia. These conditions constitute a heterogeneous group of clinical phenotypes that are linked by their common root in ribosomal dysfunction.
Fig. 2 Model for tissue-specific phenotypes of ribosomal protein mutations. (Mills, 2017)
In recent years, there has been an increase in the number of diseases identified as novel congenital ribosomopathies. These extremely rare diseases are characterized by mutations in ribosomal proteins or factors involved in ribosome biogenesis, but further studies are necessary to fully understand the contribution of altered ribosome production in their pathophysiology. These ribosomopathies are heterogeneous diseases showing generalized multisystemic symptoms, alternatively, more specific manifestations selective for one tissue or organ.
The cellular consequences of inherited RP mutations primarily include translational dysfunction (both reduced global synthesis and impaired translation of specific mRNAs) and selective activation of p53-dependent cell cycle arrest. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.
As scientists study ribosomes further, more and more important roles that ribosomes play in many different kinds of diseases have been found. Research focusing on ribosomes seems to become the key to helping open the door that reveals the truth about these diseases. As an industry-leading company, Creative Biolabs has invested a great deal of manpower, material, and financial resources to develop a comprehensive technology platform providing ribosome-related services. Our platform is dedicated to helping clients advance their projects with comprehensive ribosome relevant service including but not limited to:
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