Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein family member Survivin.
Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein family member Survivin.
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致癌 RAS 通过上调凋亡蛋白家族成员 Survivin 抑制剂的表达来促进 MYC 蛋白稳定性。
DOI：
10.1016/j.jbc.2022.102842
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发表时间：
2023-02
影响因子：
4.8
通讯作者：
Antonyak, Marc A.
中科院分区：
文献类型：
--
作者：
Chang, Wen-Hsuan;Liu, Yinzhe;Hammes, Emma A.;Bryant, Kirsten L.;Cerione, Richard A.;Antonyak, Marc A.
The small GTPase KRAS is frequently mutated in pancreatic cancer and its cooperation with the transcription factor MYC is essential for malignant transformation. The key to oncogenic KRAS and MYC working together is the stabilization of MYC expression due to KRAS activating the extracellular signal–regulated kinase 1/2, which phosphorylates MYC at serine 62 (Ser 62). This prevents the proteasomal degradation of MYC while enhancing its transcriptional activity. Here, we identify how this essential signaling connection between oncogenic KRAS and MYC expression is mediated by the inhibitor of apoptosis protein family member Survivin. This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRASG12C inhibitor Sotorasib. We went on to show that oncogenic KRAS increases Survivin expression by activating extracellular signal–regulated kinase 1/2 in pancreatic cancer cells and that treating the cells either with siRNAs targeting Survivin or with YM155, a small molecule that potently blocks Survivin expression, downregulates MYC and strongly inhibited their growth. We further determined that Survivin protects MYC from degradation by blocking autophagy, which then prevents cellular inhibitor of protein phosphatase 2A from undergoing autophagic degradation. Cellular inhibitor of protein phosphatase 2A, by inhibiting protein phosphatase 2A, helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers.
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影响因子：
8
作者：
Kerkhoff, E;Houben, R;Rapp, UR
通讯作者：
Rapp, UR
影响因子：
4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
DOI：
10.1124/jpet.110.170555
发表时间：
2010-12-01
影响因子：
3.5
作者：
Clausen, Dana M.;Guo, Jianxia;Eiseman, Julie L.
通讯作者：
Eiseman, Julie L.
影响因子：
7.3
作者：
Lanman, Brian A.;Allen, Jennifer R.;Cee, Victor J.
通讯作者：
Cee, Victor J.
DOI：
10.1158/1541-7786.mcr-13-0542
发表时间：
2014-06
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Farrell AS;Allen-Petersen B;Daniel CJ;Wang X;Wang Z;Rodriguez S;Impey S;Oddo J;Vitek MP;Lopez C;Christensen DJ;Sheppard B;Sears RC
通讯作者：
Sears RC