Department of Medical Biosciences, Pathology, Umeå University, SE-901 85 Umeå, Sweden.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
EBioMedicine. 2022 Aug;82:104155. doi: 10.1016/j.ebiom.2022.104155. Epub 2022 Jul 16.
Transforming growth factor β (TGFβ) is overexpressed in several advanced cancer types and promotes tumor progression. We have reported that the intracellular domain (ICD) of TGFβ receptor (TβR) I is cleaved by proteolytic enzymes in cancer cells, and then translocated to the nucleus in a manner dependent on the endosomal adaptor proteins APPL1/2, driving an invasiveness program. How cancer cells evade TGFβ-induced growth inhibition is unclear.
We performed microarray analysis to search for genes regulated by APPL1/2 proteins in castration-resistant prostate cancer (CRPC) cells. We investigated the role of TβRI and TRAF6 in mitosis in cancer cell lines cultured in 10% FBS in the absence of exogenous TGFβ. The molecular mechanism of the ubiquitination of AURKB by TRAF6 in mitosis and the formation of AURKB-TβRI complex in cancer cell lines and tissue microarrays was also studied.
During mitosis and cytokinesis, AURKB-TβRI complexes formed in midbodies in CRPC and KELLY neuroblastoma cells. TRAF6 induced polyubiquitination of AURKB on K85 and K87, protruding on the surface of AURKB to facilitate its activation. AURKB-TβRI complexes in patient's tumor tissue sections correlated with the malignancy of prostate cancer.
The AURKB-TβRI complex may become a prognostic biomarker for patients with risk of developing aggressive PC.
Swedish Medical Research Council (2019-01598, ML; 2015-02757 and 2020-01291, CHH), the Swedish Cancer Society (20 0964, ML), a regional agreement between Umeå University and Region Västerbotten (ALF; RV-939377, -967041, -970057, ML). The European Research Council (787472, CHH). KAW 2019.0345, and the Kempe Foundation SMK-1866; ML. National Microscopy Infrastructure (NMI VR-RFI 2016-00968).
转化生长因子β（TGFβ）在几种晚期癌症中过度表达，并促进肿瘤进展。我们曾报道过 TGFβ 受体（TβR）I 的细胞内结构域（ICD）可被癌细胞中的蛋白水解酶切割，然后以依赖内体衔接蛋白 APPL1/2 的方式转移到细胞核中，驱动侵袭程序。然而，癌细胞如何逃避 TGFβ 诱导的生长抑制尚不清楚。
我们进行了微阵列分析，以寻找 APPL1/2 蛋白在去势抵抗性前列腺癌（CRPC）细胞中调控的基因。我们研究了 TβRI 和 TRAF6 在无外源性 TGFβ 的情况下，在培养于 10%胎牛血清的癌细胞系中的有丝分裂中的作用。还研究了 TRAF6 在有丝分裂中对 AURKB 的泛素化以及 AURKB-TβRI 复合物在癌细胞系和组织微阵列中的形成的分子机制。
在 CRPC 和 KELLY 神经母细胞瘤细胞的有丝分裂和胞质分裂过程中，AURKB-TβRI 复合物在中间体中形成。TRAF6 在 AURKB 的 K85 和 K87 上诱导多泛素化，使其突出于 AURKB 表面，从而促进其激活。患者肿瘤组织切片中的 AURKB-TβRI 复合物与前列腺癌的恶性程度相关。
AURKB-TβRI 复合物可能成为具有发展侵袭性 PC 风险的患者的预后生物标志物。
瑞典医学研究理事会（2019-01598，ML；2015-02757 和 2020-01291，CHH），瑞典癌症协会（200964，ML），于默奥大学和韦斯特博腾地区之间的区域协议（ALF；RV-939377，-967041，-970057，ML）。欧洲研究理事会（787472，CHH）。KAW 2019.0345 和 Kempe 基金会 SMK-1866；ML。国家显微镜基础设施（NMI VR-RFI 2016-00968）。
Zotero 插件
