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Merck
  • Cullin-5 deficiency orchestrates the tumor microenvironment to promote mammary tumor development through CREB1-CCL2 signaling.

Cullin-5 deficiency orchestrates the tumor microenvironment to promote mammary tumor development through CREB1-CCL2 signaling.

Science advances (2023-01-21)
Si Chen, Fangyuan Shao, Jianming Zeng, Sen Guo, Lijian Wang, Heng Sun, Josh Haipeng Lei, Xueying Lyu, Shuai Gao, Qiang Chen, Kai Miao, Xiaoling Xu, Chu-Xia Deng
要旨

Breast cancer-associated gene 1 (Brca1) deficiency induces the onset of breast cancer formation, accompanied with extensive genetic alterations. Here, we used both the sleeping beauty transposon mutagenesis system and CRISPR-Cas9-mediated genome-wide screening in mice to identify potential genetic alterations that act synergistically with Brca1 deficiency to promote tumorignesis. Both approaches identified Cullin-5 as a tumor suppressor, whose mutation enabled Brca1-deficient cell survival and accelerated tumorigenesis by orchestrating tumor microenvironment. Cullin-5 suppresses cell growth through ubiquitylating and degrading adenosine 3',5'-monophosphate-responsive element binding protein 1 (CREB1), especially under protein damage condition. Meanwhile, Cullin-5 deficiency activated CREB1-CCL2 signaling and resulted in the accumulation of monocytes and polymorphonuclear myeloid-derived suppressor cells, reduction of T cells that benefit tumor progression in both Brca1-deficient cells and wild-type cells. Blocking CREB1 activity either through gene knockout or specific inhibitor treatment suppressed changes in the tumor microenvironment caused by Cullin-5 deficiency and blocked tumor progression.

材料
製品番号
ブランド
製品内容

Sigma-Aldrich
モノクロナール抗β-アクチン マウス宿主抗体, clone AC-74, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Anti-Cullin-5 (CUL5) Antibody, from rabbit, purified by affinity chromatography