New Discoveries Regarding Links between Ribosome Biogenesis and Cancer - Research Paper Example

New Discoveries Regarding Links between Ribosome Biogenesis and Cancer May 19, New Discoveries Regarding Links between Ribosome Biogenesis and Cancer According to the World Health Organization (WHO) (2015), cancer is the leading cause of death, where it composed 13% of all deaths in the world, or 7.6 million deaths in 2008. The majority of cancer deaths come from cancers of the lung, stomach, breast, colorectal, and prostate, wherein problems with the immune system interact with other body systems, depending on the kind of cancer involved (WHO, 2015 in “Cancer Mortality and Morbidity”). A distinct characteristic of cancer is the rapid production of abnormal cells that extend from their common boundaries, and which can then attack adjacent body parts and spread to other organs, through the process of metastases (WHO, 2015 in “Cancer”). Recent studies are exploring ribosome biogenesis’ role in inflammatory pathologies that include cancer (Blalock et al., 2014) and how dysregulated rRNA synthesis could contribute to or be a product of malignant cellular changes (Nguyen et al., 2015). Studying ribosome biogenesis and its dynamics and effects on malignant tumors can improve the understanding of cancer cell proliferation and may lead to more precise treatments/therapies for cancer (Blalock et al., 2014; Nguyen et al., 2015; Penzo et al., 2015). Recent Discoveries: On Ribosome Biogenesis and Cancer Ribosome biogenesis involves multiple steps, including rRNA transcription, development of pre-rRNA transcripts towards maturity, gathering of preribosomes, and RNA processing into mature ribosomes (Nguyen et al., 2015). Ribosomal DNA (rDNA) goes through the transcribing of the RNA polymerase I (Pol I) into a 47 S rRNA precursor, which later becomes processed and turns into 18 S, 5.8S, and 28 S mature rRNAs (Nguyen et al., 2015). rDNA becomes multicopy genes in arrays, wherein the number of active genes in any specific time has epigenetic regulations (Nguyen et al., 2015). Furthermore, various cellular signaling pathways connected to cell growth impact the activity of proteins that are in charge of rRNA transcription and which can be co-opted through the oncogenic processes (Nguyen et al., 2015). The following studies provide novel discoveries about the genetic expressions of different kinds of cancers. Ribosomal Gene Expression: Regulation of Genetic Expressions and Cancer Nguyen et al. (2015) studied the epigenetic and the post-transcriptional mechanisms that may give some explanation on how dysregulated rRNA synthesis could influence or be a product of malignant transformation. They learned from their studies that Akt has a function in pre-rRNA synthesis. Their findings and other research showed that the pro-cell survival PI3K/Akt axes are similarly connected to and may cause oncogenesis, even without the mTOR pathway (Blalock et al., 2014; Nguyen et al., 2015). Activated Akt has a crucial function in stimulating rRNA synthesis through boosting transcription initiation factor I (TIF-IA) expression, which happens through hindering the latter’s ubiquitination and succeeding degradation via mouse double minute 2 (Mdm2) (Nguyen et al., 2015). The result is that the TIF-IA translocates to the nucleolus, interacts with casein kinase 2 (CK2) phosphorylates and triggers TIF-IA, which produces more rDNA gene transcription (Nguyen et al., 2015). Nguyen et al. (2015) implicated that a direct target of Akt may be a novel and effective way of stopping rRNA synthesis in tumors. Furthermore, CK2 phosphorylates UBF, TIF-IA, SL1, and topoisomerase IIa, nucleolin and nucleophosmin manage the Pol I transcription at numerous levels, such as the production of transcription initiation complex, escape of promoters, and the elongation and re-launching of Pol I transcription (Nguyen et al., 2015). Inhibiting CK2 phosphorylates also stops rDNA transcription and prevents cell proliferation (Nguyen et al., 2015). Therapeutic strategies that involve the use of small molecule inhibitors can particularly regulate rRNA synthesis through direct and indirect utilization of upstream modulators and discovery of new targets in the Pol I transcription complex (Nguyen et al., 2015). Nguyen et al. (2015) concluded that some oncogenic activities can directly impact rRNA synthesis, which suggests that it can function as a downstream enabler for cancer cell production. They added that the dysregulation of rRNA synthesis can cause genomic instability, which contributes to cancer. p63 and Basonuclin 1 (BNC1) Expression Boldrup et al. (2012) learned that p63 stimulates the expression of the basal epithelial transcription factor called the Basonuclin 1 (BNC1). p63 is a homologue of the tumor suppressor p53 and is discovered to be essential to constructing epithelial structures (Boldrup et al., 2012). The TP63 gene encodes six diverse isoforms at the minimum via two promoters and gene splicing at the C-terminus (Boldrup et al., 2012). p63 has been shown to have a function in tumor formation, in particular, ∆p63 becomes an oncogene and TAp63 serves as the tumor suppressor gene (Boldrup et al., 2012). Boldrup et al. (2012) supported other studies which showed that overexpression and highly sophisticated arrays of p63 isoform expression are present in the squamous cell carcinoma of the head and neck (SCCHN). BNC1 is a significant transcription factor which regulates keratinocyte differentiation (Boldrup et al., 2012). BNC1 is an extraordinary transcription factor because it affects rRNA expression through Pol I and can also link with RNA polymerase II (Pol II) promoters (Boldrup et al., 2012). Using cell cultures, Boldrup et al. (2012) observed that BNC1 boosts ribosome production, which is closely connected with the tumor’s proliferation potential, and which also influences the expression of genes that shapes the differentiation of cells. Determining p63 as a regulator for the inducement of BNC1 in SCCHN connects the former with the development of tumors through the upward modulation of ribosomal biogenesis (Boldrup et al., 2012). In addition, regulating BNC1 through DNp63 can affect the inhibition of cell differentiation, as BNC1 affects Pol-II transcription factor, wherein the latter can stop the expression of epithelial differentiation-related proteins (Boldrup et al., 2012). They concluded that learning these mechanisms can help understand how p63 derails cell differentiation and how it is linked with ribosomal biogenesis, which is connected to tumor cell metabolism. Impacts of JHDM1B Expression Breast Cancer Cell Growth through p53 If p63 has a role in squamous cell carcinoma of the head and neck (SCCHN), Penzo et al. (2015) learned that Jumonji C histone demethylase 1B (JHDM1B) expression contributes to rRNA synthesis that is present in breast cancer through p53. They determined that higher rDNA transcription, which comes from diminished JHDM1B levels, is connected to diverse cell backgrounds and to significantly different biological results. Through RNA interference in cell cultures, they learned that the impacts of JHDM1B expression on regulating cancel cell growth rely on p53 status during in vitro and in principal human tumors (Penzo et al., 2015). Penzo et al. (2015) confirmed past studies that showed that a knockdown in JHDM1B expression promoted ribosome biogenesis. Nevertheless, the outcome was true for one cell line they tested, specifically MDA-MB-231, wherein the main difference was the p53 status (Penzo et al., 2015). Furthermore, the study discovered that JHDM1B knock-down stimulated p38-MAPK, which is a mediator for cellular stress reactions. Activating p38-MAPK launched p53 phosphorylation on some serine residues, which subsequently impacts p53 activity for particular genes, including p15 and p21 (Penzo et al., 2015). These two may be the last mediators that hinder cellular proliferation in p53 cell lines, which were considered as competent ones (Penzo et al., 2015). In addition, findings from primary breast carcinomas showed that JHDM1B expression has an inverse relationship with the nucleolar area, which suggests that it manifests ribosome biogenesis and may be connected to tumor aggressiveness (Penzo et al., 2015). Researchers noted that prognosis for breast cancer was better if the expression of JHDM1B tumor was high, instead of being low (Penzo et al., 2015). For cellular backgrounds where p53 is inactive, greater ribosome biogenesis boosts cell proliferation, which can stimulate unrestrained cancerous growth (Penzo et al., 2015). PKR in Ribosome Biogenesis In another study, Blalock et al. (2014) determined how the double-strand RNA-dependent protein kinase, PKR, serves an important function in the nuclear compartment of ribosome biogenesis. PKR is an “innate immune/inflammatory cytokine” that is linked with protein kinase and responds to different stress signals (Blalock et al., 2014). PKR phosphorylates and affects p53, restrains kB-b (IkB-b), the B56a regulatory sub-part of protein phosphatase 2A (PP2A), and affects different pathways for kinase-dependent expressions, among other functions (Blalock et al., 2014). Findings showed that 69 proteins were present in active PKR, 38 were in the inactive complex, and 13 were in both active and inactive complexes. Most of the proteins participated in ribosome biogenesis, splicing of RNA, stability of mRNA, expression of genes, and cell cycle, as well as other cell organizations that are related to normal hematopoiesis and/or hematological disease (Blalock et al., 2014). Over-expression of PKR during normal growth settings resulted to cell proliferation, while the inhibition of PKR did not result to cellular growth (Blalock et al., 2014). The study also discovered that PKR affected the expression of the proto-oncogene Myc. Myc stimulates genes that are linked to different cellular processes, such as cell growth and metabolism, and can also drive ribosome biogenesis (Nguyen et al., 2015). Particularly, inhibiting PKR expanded the expression of p64 and p67 Myc for 12 hours, due to possibly the concurrent actions of post-transcriptional and posttranslational mechanisms (Blalock et al., 2014). A higher expression of Myc p67 followed after treating tissues with the PKR inhibitor; on the opposite, overexperession of active or inactive PKR stimulated the expression of Myc p64 (Blalock et al., 2014). A sophisticated protein network affects PKR in the nucleus, depending on how PKR is catalyzed (Blalock et al., 2014). These proteins interact biologically through pathologies that are related to PKR, such as cancer (Blalock et al., 2014). Ribosomal Protein L11 and Repression of c-Myc Expression during Ribosomal Stress In continuation of the study of Myc, Challagundla et al. (2011) examined how the ribosomal protein L11 influences c-myc mRNA turnover. c-Myc activity may promote cell proliferation and tumorigenesis through its function in boosting ribosomal biogenesis (Challagundla et al., 2011). Challagundla et al. (2011) observed the dynamics involved in L11’s regulation of c-Myc levels. They learned that L11 links up with c-myc mRNA at the location of 3 untranslated region (3-UTR), which is the main component of microRNA-induced silencing complex (miRISC) argonaute 2 (Ago2). Findings also showed that L11 weakens c-myc mRNA through a new form of miRNA-mediated mechanism. They also discovered that L11-mediated c-myc mRNA decay is fundamental for c-Myc downregulation, which is part of the reaction to ribosomal stress. Challagundla et al. (2011) noted that exposing cells to different insults can produce genomic instability. They explained that the p53-dependent cell cycle serve as checkpoints that produce genomic instability during stressful situations. This confirms other studies that deregulated overactivation of c-Myc starts genomic instability, which may explain its oncogenic effects (Challagundla et al., 2011). Conclusion The complexity of understanding the regulation of rRNA synthesis is essential to learning more about cancer cell biology. Discoveries regarding ribosome biogenesis may not swiftly translate to new therapeutic insights. Future studies can focus on understanding different gene expressions for various cancers that can lead to cancer risk determination and the design of cancer-specific treatments. These treatments can result to precise medicine that can target cancer cells per se and not healthy cells and may also stop tumor cell genesis. References Blalock WL, Piazzi M, Bavelloni A, et al. Identification of the PKR Nuclear Interactome Reveals Roles in Ribosome Biogenesis, mRNA Processing and Cell Division. J Cell Physiol. 2014;229:1047-1060. Boldrup L, Coates PJ, Laurell G, Nylander K. p63 Transcriptionally regulates BNC1, a Pol I and Pol II transcription factor that regulates ribosomal biogenesis and epithelial differentiation. European Journal of Cancer (Oxford, England : 1990). 2012;48:1401. Challagundla KB, Sun X, Zhang X, et al. Ribosomal Protein L11 Recruits miR-24/miRISC To Repress c-Myc Expression in Response to Ribosomal Stress. Mol Cell Biol. 2011;31:4007-4021. Nguyen LXT, Raval A, Garcia JS, Mitchell BS. Regulation of Ribosomal Gene Expression in Cancer. J Cell Physiol. 2015;230:1181-1188. Penzo M, Casoli L, Pollutri D, et al. JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner. International Journal of Cancer. 2015;136:E272-E281. World Health Organization. Cancer mortality and morbidity. http://www.who.int/gho/ncd/mortality_morbidity/cancer_text/en/ Published 2015. Accessed May 17, 2015. World Health Organization. Cancer. http://www.who.int/mediacentre/factsheets/fs297/en/ Published 2015. Updated February 2015. Accessed May 17, 2015. Read More