Decker Joseph T, Ma Jeffrey A, Shea Lonnie D, Jeruss Jacqueline S
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Surgery, University of Michigan, Ann Arbor, MI 48109-5932, USA.
Cancers (Basel). 2021 Oct 25;13(21):5343. doi: 10.3390/cancers13215343.
TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.
转化生长因子β（TGFβ）信号传导通过促进多种细胞调节作用（包括细胞周期控制和细胞凋亡）在正常细胞中发挥肿瘤抑制功能。经典的TGFβ信号传导通过转录因子SMAD3在蛋白质C末端的磷酸化来进行。在致癌过程中，这种SMAD3的肿瘤抑制性磷酸化可能会受到抑制。细胞周期蛋白D和E的过表达以及随后细胞周期蛋白依赖性激酶2/4（CDK）的过度激活在乳腺癌中经常被观察到，并且与不良预后相关。CDK 2和4对SMAD3的非经典磷酸化导致SMAD3的肿瘤抑制功能受到抑制。因此，CDK的过度激活驱动致癌过程，并且可以作为靶点来改善临床结果。本综述聚焦于乳腺癌，并强调了在理解CDK介导的非经典SMAD3磷酸化方面的进展。具体而言，将研究异常TGFβ信号传导在致癌过程和治疗反应中的作用，以说明在细胞周期蛋白/CDK和SMAD3背景下进行治疗发现的潜力。
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