Physiological function of the Ran Binding Protein 3-Like and its prdeicted function in renal cancer

• Applicant: Professor Dr. Bayram Edemir, Ph.D.
• Subject Area: Nephrology ; Anatomy and Physiology ; Hematology, Oncology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386120064

So far information regarding the function of the Ran Binding Protein 3-Like (RanBP3L) is rare. One study shows interaction with the TGF-ß/BMP pathway. We were able to show that the expression of RanBP3L is induced by hyper osmolality. During the initial funding period we were able to show that its expression is induced by the action of Nuclear Factor of Activated T-Cells (NFAT5). Deletion of RanBP3L was associated with massive morphological and functional changes, also in the gene expression profile. Taken together these data implicate a phenotype that is associated with tumor cells. In two studies we were able to show that hyper osmolality regulated genes showed invers expression in samples from patients with clear cell renal carcinoma (ccRCC) and that this is also prognostic for patients’ survival. Also high expression of RanBP3L is favorable for clinical outcome and expression is significantly lower in primary tumor vs. solid tissue normal. The expression gets even lower with increased staging. This was also evident when we compare it with the PANCAN cohort from The Cancer Genome Atlas. High expression of RanBP3L is associated with overall survival and expression level is highest in normal tissue and decreases from primary tumor to metastatic samples. These results implicate a major function of RanBP3L in tumor biology. Therefore, information regarding physiological function and regulation of expression of RanBP3L are important. Our preliminary results show that functional deletion induces the expression of SPARC and suppression of SH3GL2. High SPARC expression is prognostic unfavorable in ccRCC while high SH3GL2 is prognostic favorable. Within this proposal we will analyze if SPARC expression is contributes to the observed phenotype. We will also analyze the contribution of TGF-ß and cJUN pathway since they interfere with SOPARC expression. We will further analyze the expression pattern of RanBP3L with SPARC, SH3GL2 and other factors in primary ccRCC samples. The characterization of a RanBP3L knock out mice finally will give hints about in vivo function of RanBP3L. These analyzes will help for a better understanding of the physiological function of RanBP3L and pathophysiological function in ccRCC. If RanBP3L should have functions related to a tumorsupressor the induction of its expression might represent a therapeutic option which could be done by activation of NFAT5.

• DFG Programme: Research Grants