Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell-Cycle Arrest, but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity: Implications in Diamond Blackfan Anemia
Year: 2013
Type: article
Abstract: Humans have evolved elaborate mechanisms to activate p53 in response to insults that lead to cancer, including the binding and inhibition of Hdm2 by 60S ribosomal proteins (RPs) RPL5 and RPL11.This same mechanism appears to be activated upon impaired ribosome biogenesis, highlighted by an inherited congenital bone marrow failure syndrome Diamond Blackfan Anemia (DBA), characterized by normochromic macrocytic anemia and heterozygous mutations or deletions involving several ribosomal protein (RP) genes including RPS19, RPS24, RPL35a, RPS17, RPS7, RPS10, RPS26, RPL15, RPL5 and RPL11.As loss of RPL5/RPL11 abrogates ribosome biogenesis and protein synthesis to the same extent as other essential 60S RPs, we reasoned their loss would induce a p53-independent cellcycle checkpoint.Unexpectedly, we found that their depletion in primary human lung fibroblasts failed to induce cell-cycle arrest, but strongly suppressed cell-cycle progression.We show that the effects on cell-cycle progression stemmed from reduced ribosome content and translational capacity, which suppressed the accumulation of cyclins at the translational level.Thus, unlike other tumor suppressors, RPL5/RPL11 play an essential role in normal cell proliferation, a function cells have evolved to rely on in lieu of a cell-cycle checkpoint.We have further set out to determine whether the same mechanism is applicable in erythroid progenitor cells.We find that levels of p53 status vary greatly within erythroid progenitor cells, as shown by immunohistochemistry (IHC) in a limited number of DBA patient bone marrow biopsy slides.Preliminary studies using erythroid progenitor cells differentiated from RPL11 shRNA infected CD34 + cells revealed a lack of p53 induction, consistent with our observation in primary lung fibroblasts, iii suggesting a p53 independent mechanism in DBA patients with RPL5/RPL11 mutations.
Author: Teng Teng
Institution: University of Cincinnati
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2285457604