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The Promoter Region of the Proto-Oncogene MST1R Contains the Main Features of G-Quadruplexes Formation.

ABSTRACT: MST1R (RON) is a receptor of the MET tyrosine kinase receptor family involved in several cancers such as pancreas, breast, ovary, colon, and stomach. Some studies have shown that overexpression of MST1R increases the migratory and invasive properties of cancer cells. The promoter region of the oncogene MST1R is enriched in guanine residues that can potentially form G-quadruplexes (G4s), as it was observed in other oncogenic promoters such as KRAS and c-MYC. There is abundant literature that links the presence of G4s in promoter regions of oncogenes to diverse gene regulation processes that are not well understood. In this work, we have studied the reverse and forward sequence of MST1R promoter region using the G4Hunter software and performed biophysical studies to characterize the best scored sequences.

SUBMITTER: Robert C

PROVIDER: S-EPMC9653784 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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The Promoter Region of the Proto-Oncogene MST1R Contains the Main Features of G-Quadruplexes Formation.

Robert Coralie C Marquevielle Julien J Salgado Gilmar F GF

International journal of molecular sciences 20221026 21

MST1R (RON) is a receptor of the MET tyrosine kinase receptor family involved in several cancers such as pancreas, breast, ovary, colon, and stomach. Some studies have shown that overexpression of MST1R increases the migratory and invasive properties of cancer cells. The promoter region of the oncogene MST1R is enriched in guanine residues that can potentially form G-quadruplexes (G4s), as it was observed in other oncogenic promoters such as KRAS and c-MYC. There is abundant literature that link ...[more]

PMID: 36361696

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Project description:In human and mouse, the promoter of the KRAS gene contains a nuclease hypersensitive polypurine-polypyrimidine element (NHPPE) that is essential for transcription. An interesting feature of the polypurine G-rich strand of NHPPE is its ability to assume an unusual DNA structure that, according to circular dichroism (CD) and DMS footprinting experiments, is attributed to an intramolecular parallel G-quadruplex, consisting of three G-tetrads and three loops. The human and mouse KRAS NHPPE G-rich strands display melting temperature of 64 and 73 degrees C, respectively, as well as a K+-dependent capacity to arrest DNA polymerase. Photocleavage and CD experiments showed that the cationic porphyrin TMPyP4 stacks to the external G-tetrads of the KRAS quadruplexes, increasing the T(m) by approximately 20 degrees C. These findings raise the intriguing question that the G-quadruplex formed within the NHPPE of KRAS may be involved in the regulation of transcription. Indeed, transfection experiments showed that the activity of the mouse KRAS promoter is reduced to 20% of control, in the presence of the quadruplex-stabilizing TMPyP4. In addition, we found that G-rich oligonucleotides mimicking the KRAS quadruplex, but not the corresponding 4-base mutant sequences or oligonucleotides forming quadruplexes with different structures, competed with the NHPPE duplex for binding to nuclear proteins. When vector pKRS-413, containing CAT driven by the mouse KRAS promoter, and KRAS quadruplex oligonucleotides were co-transfected in 293 cells, the expression of CAT was found to be downregulated to 40% of the control. On the basis of these data, we propose that the NHPPE of KRAS exists in equilibrium between a double-stranded form favouring transcription and a folded quadruplex form, which instead inhibits transcription. Such a mechanism, which is probably adopted by other growth-related genes, provides useful hints for the rational design of anticancer drugs against the KRAS oncogene.

Dataset Information

The Promoter Region of the Proto-Oncogene MST1R Contains the Main Features of G-Quadruplexes Formation.

Publications

The Promoter Region of the Proto-Oncogene MST1R Contains the Main Features of G-Quadruplexes Formation.

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