LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1
biorxiv(2020)
摘要
Large-scale sequencing studies on glioblastoma have identified numerous genetic alterations. Leucine-zipper-like transcription regulator 1 ( LZTR1 ) is inactivated by non-synonymous mutations and copy number losses, suggesting that it is a tumor suppressor in glioblastoma. However, how LZTR1 mutations contribute to glioblastoma pathogenesis remains poorly understood. Here, we revealed that LZTR1, as an adaptor of the CUL3 E3 ubiquitin ligase complex, recognizes and triggers ubiquitin-dependent degradation of oncoprotein RIT1, a RAS-like GTPase. Wild-type LZTR1 suppresses glioblastoma cell proliferation and migration by inactivating the MAPK/ERK signaling pathway in a RIT1-dependent manner. However, the effects were abrogated by the glioblastoma-associated LZTR1 mutations. Our findings revealed the underlying molecular mechanism of LZTR1 mutations-driven glioblastoma, and provide novel therapeutic target for LZTR1 mutations-driven glioblastoma.
* ### ABBREVIATIONS
LZTR1
: leucine-zipper-like transcription regulator 1
RIT1
: RAS-like without CAAX1
ATCC
: American Type Culture Collection
siRNA
: small interfering RNA
shRNA
: short hairpin RNA
CCK-8
: Cell Counting Kit-8
qRT-PCR
: quantitative real-time polymerase chain reaction
BLI
: bioluminescence imaging
IP
: immunoprecipitation
DN
: dominant negative
OS
: overall survival
PFS
: progression-free survival
TCGA
: the cancer genome atlas
CGGA
: Chinese glioma genome atlas
GBM
: glioblastoma
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关键词
lztr1 inactivation,oncoprotein rit1,glioblastoma
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