F-box protein specificity for g1 cyclins is dictated by subcellular localization.
F-box protein specificity for g1 cyclins is dictated by subcellular localization.
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DOI：
10.1371/journal.pgen.1002851
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Benanti JA
中科院分区：
文献类型：
--
作者：
Landry BD;Doyle JP;Toczyski DP;Benanti JA
Levels of G1 cyclins fluctuate in response to environmental cues and couple mitotic signaling to cell cycle entry. The G1 cyclin Cln3 is a key regulator of cell size and cell cycle entry in budding yeast. Cln3 degradation is essential for proper cell cycle control; however, the mechanisms that control Cln3 degradation are largely unknown. Here we show that two SCF ubiquitin ligases, SCFCdc4 and SCFGrr1, redundantly target Cln3 for degradation. While the F-box proteins (FBPs) Cdc4 and Grr1 were previously thought to target non-overlapping sets of substrates, we find that Cdc4 and Grr1 each bind to all 3 G1 cyclins in cell extracts, yet only Cln3 is redundantly targeted in vivo, due in part to its nuclear localization. The related cyclin Cln2 is cytoplasmic and exclusively targeted by Grr1. However, Cdc4 can interact with Cdk-phosphorylated Cln2 and target it for degradation when cytoplasmic Cdc4 localization is forced in vivo. These findings suggest that Cdc4 and Grr1 may share additional redundant targets and, consistent with this possibility, grr1Δ cdc4-1 cells demonstrate a CLN3-independent synergistic growth defect. Our findings demonstrate that structurally distinct FBPs are capable of interacting with some of the same substrates; however, in vivo specificity is achieved in part by subcellular localization. Additionally, the FBPs Cdc4 and Grr1 are partially redundant for proliferation and viability, likely sharing additional redundant substrates whose degradation is important for cell cycle progression. Most cells only divide when they receive the proper cues. When a cell receives a signal to divide, levels of G1 cyclin proteins increase and drive entry into the cell division cycle. Overexpression of G1 cyclins can drive cells into the cell cycle inappropriately and thus may contribute to the hyperproliferation of cancer cells. Despite the importance of controlling G1 cyclin levels, the mechanisms regulating the degradation of these proteins are not well understood. We have now elucidated the mechanism of degradation of the yeast G1 cyclin Cln3. In contrast to related cyclins in yeast, Cln3 is targeted for degradation by two redundant pathways, which act to keep Cln3 levels extremely low. This finding may have implications for understanding how G1 cyclins are degraded in human cells and how expression of G1 cyclins may be misregulated during cancer development.
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