Extensive studies have demonstrated that the underlying cause of Diamond Blackfan anemia (DBA) is hypomorphic mutations in ribosomal protein (rp) genes. Patients with this disease present with an erythroid anemia, which has the propensity to progress to a wide range of cancers, particularly acute myeloid leukemia and osteosarcomas. Recently our laboratory has provided a model to explain the anemia, and, potentially the cancer. We first showed that after disruption of either 40S, or 60S ribosome biogenesis, p53 levels increase due to the binding of rpL11, a 60Srp, to HDm2, leading to a G1cell cycle arrest. However, in the case of 40S, but not 60S ribosome biogenesis, this response requires the translational upregulation of rpL11, to generate sufficient protein to bind to HDm2, in the face of continued 60S ribosome biogenesis. In parallel, it is known that rp genes, including rpL11, are direct transcriptional targets of c-Myc, a master regulator of cell proliferation and differentiation, and that rpL11 acts in a negative feedback loop to block c-Myc target genes. In preliminary studies we find that rpL11 controls c-Myc transcription. These studies have led us to hypothesize that a complex containing rpL11, is upregulated in response to disruption of 40S ribosome biogenesis, to induce p53 cell cycle arrest and suppress c-Myc expression, preventing tumor progression. Likewise loss of this checkpoint could explain the propensity of DBA patients to progress to cancer. To address the first part of this hypothesis, the role of rpL11 in anemia, we have designed three aims (1) To identify the signaling components involved in the upregulation of rpL11 (2) To determine the mechanism of rpL11 induced inhibition of HDm2 in response to disruption of ribosome biogenesis and (3) Develop a mouse model to replicate the DBA phenotype to study the action of known therapies and to develop novel treatments.
Field of science
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
- /medical and health sciences/clinical medicine/cancer
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