A proliferating cell expends most of its energy in the biogenesis of nascent ribosomes. The increased number of ribosomes provides the translational capacity required for the cell to synthesize the full complement of proteins necessary to enter the mitotic cell cycle and divide. The importance of ribosome biogenesis to cell proliferation is underscored by the fact that a lesion in ribosome biogenesis alters the ratio of ribosomes to mRNA, which eventually modifies the pattern of translation and the genetic program, resulting in aberrant growth. Given these observations, we initially predicted that cells would have evolved a checkpoint to monitor nascent ribosome biogenesis. The importance of this concept to human pathology has been demonstrated in two haemopoietic disorders, 5q- syndrome and Diamond Blackfan Anemia (DBA), which are characterized by hypomorphic mutations or deletions in ribosomal protein (rp) genes. Patients with these diseases first develop myelodysplasias, but have the propensity to progress to a wide range of cancers later in life, particularly acute myeloid leukemia (AML). The concept that rp genes act as haploinsufficient tumor suppressors initially came from studies in model systems, including Drosophila and zebrafish. Recent studies from this laboratory have provided a model to explain both the myelodysplasia and the potential to develop cancer. We showed that upon disruption of either 40S or 60S ribosome biogenesis there is an upregulation of p53 mediated by the binding of the 60S rps, rpL5 and rpL11, to human double minute 2 (MDM2 or Hdm2), leads to G1 cell-cycle arrest. However, in circumstances where 40S, but not 60S, ribosome biogenesis is impaired, this effect requires the translational upregulation of rpL5 and rpL11 to generate sufficient protein to bind to Hdm2 in the face of continued 60S ribosome biogenesis and a decrease in global protein synthesis. The translational upregulation of rpL5 and rpL11 is dependent on the 5' TOP sequence, which acts as translational repressor, and resides at the transcriptional start site of rp mRNAs. Loss of this checkpoint is most likely responsible for the propensity of 5q- syndrome and DBA patients to develop AML. The importance of this checkpoint in p53 positive tumors is underscored by two findings: (i) the extent of tumor progression directly parallels nucleolar size and RNA polymerase 1 (Pol 1) activity and (ii) actinomycin D, which at low concentrations, selectively inhibits RNA Pol 1, arrests p53/MDM2 wild type (WT) tumor cells in G1. Together, these observations have led us to hypothesize that the rpL5/rpL11 complex is upregulated in response to impaired ribosome biogenesis to induce p53 cell-cycle arrest and to prevent tumor progression. These studies are relevant to tumor biology as they are designed to elucidate the mechanism by which impaired ribosome biogenesis mediates cell cycle progression, the identification of components in addition to rp5/rpL11 which mediate this response, and the role of general translation versus the p53 checkpoint in controlling tumor progression beyond 5q- syndrome and DBA, which will aid in the development of novel cancer treatments.
Normal cell division requires the production of new ribosomes, the cellular structures responsible for protein synthesis, so that each new daughter cell will have adequate capacity to produce protein to grow. Cells respond to defects in ribosome production by shutting down cell division and, in this way, prevent abnormal cell growth and tumor formation. The project proposed here will explore a cellular anti-tumor mechanism, which is lost in cancer progression, and exploit information from these studies that will help in designing new cancer treatments.
|Arif, Abul; Terenzi, Fulvia; Potdar, Alka A et al. (2017) EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542:357-361|
|Gentilella, Antonio; Morón-Duran, Francisco D; Fuentes, Pedro et al. (2017) Autogenous Control of 5?TOP mRNA Stability by 40S Ribosomes. Mol Cell 67:55-70.e4|
|Cortes, Constanza L; Veiga, Sonia R; Almacellas, Eugènia et al. (2016) Effect of low doses of actinomycin D on neuroblastoma cell lines. Mol Cancer 15:1|
|Yi, Sang Ah; Um, Sung Hee; Lee, Jaecheol et al. (2016) S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis. Mol Cell 62:443-452|
|Gentilella, Antonio; Kozma, Sara C; Thomas, George (2015) A liaison between mTOR signaling, ribosome biogenesis and cancer. Biochim Biophys Acta 1849:812-20|
|Teng, Teng; Mercer, Carol A; Hexley, Philip et al. (2013) Loss of tumor suppressor RPL5/RPL11 does not induce cell cycle arrest but impedes proliferation due to reduced ribosome content and translation capacity. Mol Cell Biol 33:4660-71|
|Donati, Giulio; Peddigari, Suresh; Mercer, Carol A et al. (2013) 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2-p53 checkpoint. Cell Rep 4:87-98|
|Fumagalli, Stefano; Di Cara, Alessandro; Neb-Gulati, Arti et al. (2009) Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction. Nat Cell Biol 11:501-8|