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Studies on the effect of c-Cbl exon skipping on αPix-mediated cell migration and invasion of glioma cells : c-Cbl 엑손 건너뛰기가 αPix에 의해 매개되는 뇌종양 세포의 이동과 침투에 미치는 영향에 대한 연구

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자연과학대학 생명과학부
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서울대학교 대학원
c-CblαPixgliomaexon skippingconfluencyhypoxia
학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2015. 2. 정진하.
c-Cbl, a RING-type ubiquitin E3 ligase, down-regulates receptor tyrosine kinases, including EGF receptor, and inhibits cell proliferation, migration, and invasion. Moreover, mutations of c-Cbl are frequently found in patients with myeloid neoplasm. Therefore, c-Cbl is known as a tumor suppressor. αPix, a potent mediator of cell migration, is highly expressed only in proliferative and mobile cells, including immune cells, and is up-regulated in certain invasive tumors, such as glioblastoma multiforme (GBM). Here, I showed that a part of the RING domain in c-Cbl is skipped in rat C6 and human A172 glioma cells and brain tissues of several glioblastoma patients. Specifically, these cells and tissues generated c-Cbl that lacks the amino acid sequences corresponding to exon-9 or both exon-9 and exon-10, termed type I and type II exon skipping, respectively. Significantly, both types of the exon skipping prevented c-Cbl-mediated ubiquitination and proteasomal degradation of αPix, resulting in dramatic accumulation of αPix. Moreover, the c-Cbl exon skipping promoted EGF signaling and αPix-mediated cell migration and invasion. However, analysis of the c-Cbl genomic DNA sequence revealed that no putative splice site mutation exists between exon-8 and exon-11. Furthermore, both types of the exon skipping could be seen only when C6 and A172 cells were grown to confluent state (i.e., in contact inhibition) or under hypoxia conditions, as analyzed by using a mini-gene harboring the genomic DNA from exon-7 to exon-11. These results suggest that unknown defect of trans-element(s) in C6 and A172 cells, likely also in the tissues from glioma patients, is responsible for the abnormal exon skipping, which in turn allows the glioma cells to overcome contact inhibition and hypoxic condition. In summary, these findings indicate that the c-Cbl exon skipping contributes to human glioma and its malignant behavior.
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