MYC is known to regulate cell size and protein synthesis rates, and cells with deregulated MYC expression show an increase in both. The significance of these effects in tumorigenesis is not clear, so Ruggero and colleagues crossed lymphoma-prone Eμ–Myc heterozygous mice with mice that are heterozygous for the ribosomal protein L24 and therefore have reduced rates of protein synthesis. They found that normal rates of protein synthesis and cell size were restored in the Eμ–Myc/+;L24+/− mice compared with Eμ–Myc/+ mice. Moreover, expression of G1–S phase proteins transcriptionally regulated by MYC was normal in Eμ–Myc/+;L24+/− B lymphocytes, but fewer of these cells were in S-phase compared with B lymphocytes from Eμ–Myc/+ mice. The Eμ–Myc/+;L24+/− mice also had higher rates of B-lymphocyte apoptosis than Eμ–Myc/+ mice. The authors suggest that these findings indicate that increased levels of protein synthesis as a consequence of MYC deregulation can regulate cell cycle transition independently from the transcriptional control of cell cycle targets by MYC, and that normal rates of protein synthesis are not enough to override the induction of apoptosis by MYC. In agreement with these findings, fewer Eμ–Myc/+;L24+/− mice developed lymphomas.
By studying synchronized B lymphocytes from both Eμ–Myc/+;L24+/− mice and Eμ–Myc/+ mice, the authors spotted a notable difference during mitosis. Normally, cap-dependent translation is decreased and cap-independent translation of a few proteins that are crucial for the regulation of mitosis is evident. Cap-independent translation remains suppressed in Eμ–Myc/+ mice and cap-dependent translation is maintained. Moreover, the authors found that cap-independent translation of cyclin dependent kinase 11 (Cdk11; also known as
Cdc2l6
) is impaired in Eμ–Myc/+ cells but is normal in cells from Eμ–Myc/+;L24+/− mice. In line with CDK11 ensuring accurate mitosis, cells from Eμ–Myc/+ mice have supernumerary centrosomes (which are associated with genomic instability); cells from Eμ–Myc/+;L24+/− mice do not display such defects. In agreement with this, tumours from Eμ–Myc/+ mice showed chromosomal abnormalities and this was less evident in tumours from Eμ–Myc/+;L24+/− mice.
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