Year: 2024
Type: conference-abstract
Abstract: RAB8A is a small Ras-related GTPase and member of Ras oncogene family. The cellular functions of RAB8A include regulation of protein trafficking and secretion. Increased expression of RAB8A has been observed in breast, cervical, esophageal, and endometrial cancer, and functional data suggest that RAB8A acts as an oncogene in these malignancies. Regulation of the RAB8A expression in leukemia is still unknown. The objective of the study is to identify the signaling pathways that regulate expression of RAB8A. Here we present data that the transcription of RAB8A is regulated by Casein Kinase II (CK2) signal transduction pathway via the Ikaros protein in B-cell acute lymphoblastic leukemia (B-ALL). Ikaros is a C2H2 zinc finger, DNA-binding proteins, that acts as a tumor suppressor in leukemia. Global genome-wide DNA binding analysis using ChIP-seq demonstrated increased occupancy of Ikaros at promoter of the RAB8A gene in B-ALL cell lines and in primary B-ALL cells. The role of Ikaros in regulation of RAB8A transcription in B-ALL was determined by gain-of-function and loss-of-function experiments. Overexpression of Ikaros in B-ALL in human B-ALL cells resulted in increased Ikaros binding to the RAB8A promoter and decreased RAB8A transcription. In contrast, knockdown of Ikaros with shRNA abolished Ikaros binding to the RAB8A promoter and resulted in increased RAB8A expression. These data suggest that Ikaros fuctions as a transcriptional repressor of RAB8A. Our previous studies showed that CK2 kinase directly phosphorylates Ikaros and impairs its function as transcriptional regulator. We tested whether phosphorylation by CK2 regulates Ikaros' function as a RAB8A repressor in B-ALL. Treatment of B-ALL cells with a specific CK2 inhibitors, CX-4945, resulted in increased Ikaros binding at the RAB8A promoter and reduced RAB8A expression. Both wildtype Ikaros and Ikaros phosphoresistant mutants repress RAB8A transcription in luciferase reporter assays, while phosphomimetic Ikaros mutants at CK2 phosphorylation sites lost the ability to repress RAB8A transcription. These data demonstrate that CK2 regulates transcription of RAB8A in B-ALL via Ikaros and suggest a mechanism by which CK2 signaling regulates GTPase activity in leukemia. Four Diamonds Foundation.
Source: Journal of Biological Chemistry
Institutions: Pennsylvania State University, University of Kentucky
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,800
OpenAlex ID: W4393167966