Stabilization of the c-Myc Protein by CAMKIIγ Promotes T Cell Lymphoma.,Cancer Cell

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Stabilization of the c-Myc Protein by CAMKIIγ Promotes T Cell Lymphoma.
Cancer Cell ( IF 48.8 ) Pub Date : 2017-07-10 , DOI: 10.1016/j.ccell.2017.06.001
Ying Gu ₁ , Jiawei Zhang ₁ , Xiaoxiao Ma ₂ , Byung-Wook Kim ₂ , Hailong Wang ₁ , Jinfan Li ₃ , Yi Pan ₄ , Yang Xu ₅ , Lili Ding ₁ , Lu Yang ₆ , Chao Guo ₆ , Xiwei Wu ₆ , Jun Wu ₇ , Kirk Wu ₁ , Xiaoxian Gan ₁ , Gang Li ₁ , Ling Li ₈ , Stephen J Forman ₉ , Wing-Chung Chan ₁₀ , Rongzhen Xu ₅ , Wendong Huang ₂

Affiliation

Molecular and Cellular Biology of Cancer Program & Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Molecular and Cellular Biology of Cancer Program & Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Department of Hematology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
The Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Division of Hematopoietic Stem Cell & Leukemia Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Pathology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

Although high c-Myc protein expression is observed alongside MYC amplification in some cancers, in most cases protein overexpression occurs in the absence of gene amplification, e.g., T cell lymphoma (TCL). Here, Ca²⁺/calmodulin-dependent protein kinase II γ (CAMKIIγ) was shown to stabilize the c-Myc protein by directly phosphorylating it at serine 62 (S62). Furthermore, CAMKIIγ was shown to be essential for tumor maintenance. Inhibition of CAMKIIγ with a specific inhibitor destabilized c-Myc and reduced tumor burden. Importantly, high CAMKIIγ levels in patient TCL specimens correlate with increased c-Myc and pS62-c-Myc levels. Together, the CAMKIIγ:c-Myc axis critically influences the development and maintenance of TCL and represents a potential therapeutic target for TCL.

中文翻译：

CAMKIIγ 对 c-Myc 蛋白的稳定促进 T 细胞淋巴瘤。

尽管在一些癌症中观察到高c-Myc蛋白表达与MYC扩增同时发生，但在大多数情况下，蛋白过度表达发生在没有基因扩增的情况下，例如T细胞淋巴瘤(TCL)。此处，Ca ²⁺ /钙调蛋白依赖性蛋白激酶 II γ (CAMKIIγ) 通过直接磷酸化丝氨酸 62 (S62) 来稳定 c-Myc 蛋白。此外，CAMKIIγ被证明对于肿瘤维持至关重要。用特定抑制剂抑制 CAMKIIγ 会破坏 c-Myc 的稳定性并减少肿瘤负荷。重要的是，患者 TCL 标本中的高 CAMKIIγ 水平与 c-Myc 和 pS62-c-Myc 水平升高相关。总之，CAMKIIγ:c-Myc 轴严重影响 TCL 的发育和维持，并代表 TCL 的潜在治疗靶点。

更新日期：2017-07-11

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