Abstract
Cell growth is coupled to cell-cycle progression in mitotically proliferating mammalian cells, but the underlying molecular mechanisms are not well understood. CyclinD-Cdk4/6 is known to phosphorylate RB to promote S-phase entry, but recent work suggests they have additional functions. We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. Pharmacological inhibition of Cdk4/6 leads to a rapid, TSC2-dependent reduction of mTORC1 activity in multiple human and mouse cell lines, including breast cancer cells. By simultaneously driving mTORC1 and E2F, CyclinD-Cdk4/6 couples cell growth to cell-cycle progression. Consistent with this, we see that mTORC1 activity is cell cycle dependent in proliferating neural stem cells of the adult rodent brain. We find that Cdk4/6 inhibition reduces cell proliferation partly via TSC2 and mTORC1. This is of clinical relevance, because Cdk4/6 inhibitors are used for breast cancer therapy.
Highlights
Cell growth and cell proliferation are two processes that are biologically separable
Inhibition of Cdk4/6 Leads to Rapid Inhibition of mTORC1 in Multiple Cell Lines Because we previously showed that Cdk4 promotes mTORC1 activity in Drosophila (Romero-Pozuelo et al, 2017), we asked whether this is the case in mammalian cells
Cdk4/6 inhibition led to reduced S6K phosphorylation in MCF7, SUSA, HEK293T, T98G, and mouse embryonic fibroblasts (MEFs) cells
Summary
Cell growth (the accumulation of mass) and cell proliferation (progression through the cell cycle) are two processes that are biologically separable. Cell growth and cell proliferation are often linked and exquisitely coordinated during standard mitotic proliferation of most mammalian cells, resulting in mass doubling every cell cycle so that the population cell size stays constant. In yeast, this occurs at least partly via two cell-cycle checkpoints, one at the G1/S transition, known as START, and one at the G2/M transition (Rupes, 2002). We propose here that Cdk4/6 plays an important role in this process. (Because Cdk and Cdk associate with the same cyclins and have overlapping functions, we refer to them together as Cdk4/6)
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