Loss of tumor suppressor RPL5/RPL11 does not induce cell cycle arrest but impedes proliferation due to reduced ribosome content and translation capacity.
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.
Division of Hematology and Oncology, Department of Internal Medicine.
Teng
T
Teng
Carol A
CA
Mercer
Philip
P
Hexley
George
G
Thomas
Stefano
S
Fumagalli
D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056751:Cyclin A2 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C503721:CCNA2 protein, human; C475820:CCNE1 protein, human; D056751:Cyclin A2; D019927:Cyclin E; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C549166:ribosomal protein L5, human