CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer.
CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer.
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DOI：
10.1002/emmm.201202341
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发表时间：
2013-07
影响因子：
11.1
通讯作者：
Sangfelt, Olle
中科院分区：
文献类型：
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作者：
Cepeda, Diana;Ng, Hwee-Fang;Sharifi, Hamid Reza;Mahmoudi, Salah;Soto Cerrato, Vanessa;Fredlund, Erik;Magnusson, Kristina;Nilsson, Helen;Malyukova, Alena;Rantala, Juha;Klevebring, Daniel;Vinals, Francesc;Bhaskaran, Nimesh;Zakaria, Siti Mariam;Rahmanto, Aldwin Suryo;Grotegut, Stefan;Nielsen, Michael Lund;Szigyarto, Cristina Al-Khalili;Sun, Dahui;Lerner, Mikael;Navani, Sanjay;Widschwendter, Martin;Uhlen, Mathias;Jirstrom, Karin;Ponten, Fredrik;Wohlschlegel, James;Grander, Dan;Spruck, Charles;Larsson, Lars-Gunnar;Sangfelt, Olle
SCF（Skp 1/Cul 1/F-box）泛素连接酶通过靶向泛素化的关键蛋白而作为细胞内稳态的主要调节剂。在这里，我们确定了一个迄今为止未表征的F盒蛋白，FBXO 28，控制MYC依赖的转录非蛋白水解泛素化。SCFFBXO 28的活性和稳定性在细胞周期中通过CDK 1/2介导的FBXO 28磷酸化来调节，这是其有效的MYC泛素化和下游MYC途径增强所必需的。FBXO 28的缺失或不能支持MYC泛素化的F-box突变体的过表达导致MYC驱动的转录、转化和肿瘤发生的损害。最后，在人类乳腺癌中，FBXO 28的高表达和磷酸化是预后不良的强有力的独立预测因素。总之，我们的数据表明，SCFFBXO 28在细胞周期中将CDK活性传递给MYC功能中起着重要作用，强调CDK-FBXO 28-MYC轴是MYC驱动的癌症（包括乳腺癌）的潜在分子药物靶标。
SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer.
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影响因子：
--
作者：
Cope GA;Deshaies RJ
通讯作者：
Deshaies RJ
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M
影响因子：
11.4
作者：
Bouchard, C;Marquardt, J;Eilers, M
通讯作者：
Eilers, M
DOI：
10.1073/pnas.0900121106
发表时间：
2010-01-05
影响因子：
11.1
作者：
Hydbring, Per;Bahram, Fuad;Larsson, Lars-Gunnar
通讯作者：
Larsson, Lars-Gunnar
影响因子：
5.3
作者：
Faiola, F;Liu, XH;Martinez, E
通讯作者：
Martinez, E