Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

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 the 60S ribosomal proteins (RPs) RPL5 and RPL11. This same mechanism appears to be activated upon impaired ribosome biogenesis, a risk factor for cancer initiation. As loss of RPL5/RPL11 abrogates ribosome biogenesis and protein synthesis to the same extent as loss of other essential 60S RPs, we reasoned the loss of RPL5 and RPL11 would induce a p53-independent cell cycle 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.

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ACKNOWLEDGMENTS

Flow cytometry was performed at Shriners Hospitals for Children, Cincinnati, OH, supported by a grant from the Shriners of North America (SSF 84070). G.T. is supported by grants from the Spanish Ministry of Science and Innovation (SAF2011-24967), the Instituto de Salud Carlos III (ISIS) (IIS10/00015/P), the CIG European Commission (PCIG10-GA-2011-304160), the Red Temática de Investigación Cooperativa en Cáncer (RTICC-R012/0036/0049), the NIH/NIDDK (1RC1-DK087680), and NCI/NIH (R01CA138647). S.F. is supported by grants from the Ligue Contre le Cancer (RS13/75-36) and the Agence Nationale de la Recherche (ANR-12-BSV2-0006-01).

We are indebted to G. Doerman for preparing the figures.