Yamen Abu Ahmad

Bio: Yamen Abu Ahmad is an academic researcher from Rappaport Faculty of Medicine. The author has contributed to research in topics: Ubiquitin ligase & RNF4. The author has co-authored 1 publications.

From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

Abstract: A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of “degradation-resistant” cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.

The roles of E3 ligases in Hepatocellular carcinoma.

Abstract: Hepatocarcinogenesis is a complex multistep biological process involving genetic and epigenetic alterations that are accompanied by activation of oncoproteins and inactivation of tumor suppressors, which in turn results in Hepatocellular carcinoma (HCC), one of the common tumors with high morbidity and mortality worldwide. The ubiquitin-proteasome system (UPS) is the key to protein degradation and regulation of physiological and pathological processes, and E3 ligases are key enzymes in the UPS that contain a variety of subfamily proteins involved in the regulation of some common signal pathways in HCC. There is growing evidence that many structural or functional dysfunctions of E3 are engaged in the development and progression of HCC. Herein, we review recent research advances in HCC-associated E3 ligases, describe their structure, classification, functional roles, and discuss some mechanisms of the abnormal activation or inactivation of the HCC-associated signal pathway due to the binding of E3 to known substrates. In addition, given the success of proteasome inhibitors in the treatment of malignant cancers, we characterize the current knowledge and future prospects for targeted therapies against aberrant E3 in HCC.

UBE2B promotes ovarian cancer growth via promoting RAD18 mediated ZMYM2 monoubiquitination and stabilization

Abstract: ABSTRACT Ubiquitin-conjugating enzyme E2 B (UBE2B) can form a heterodimer with ubiquitin E3 ligase RAD18. In this study, we aimed to explore new substrates of the UBE2B/RAD18 complex and their regulatory effects in ovarian cancer. Protein physical interactions were predicted using GeneMANIA. Serial sections of commercial ovarian cancer tissue arrays were used to check the protein expression of UBE2B, RAD18, and ZMYM2. Immunofluorescence staining and co-immunoprecipitation assays were performed to check their location and interactions. Cycloheximide chase assay was applied to explore the influence of UBE2B and RAD18 on ZMYM2 degradation. Xenograft tumor models were constructed to assess the influence of the UBE2B-ZMYM2 axis on in vivo tumor growth. A strong positive correlation between UBE2B and ZMYM2 and a moderate positive correlation between RAD18 and ZMYM2 were observed in 23 ovarian cancer cases. In CAOV4 and OVCAR3 cells, myc-ZMYM2 interacted with UBE2B and RAD18. UBE2B and ZMYM2 could be detected in the samples immunoprecipitated by anti-RAD18. UBE2B overexpression or knockdown did not alter ZMYM2 mRNA expression. UBE2B overexpression increased ZMYM2 monoubiquitination but reduced its polyubiquitination. RAD18 knockdown impaired UBE2B-induced ZMYM2 monoubiquitination. UBE2B overexpression significantly enhanced the stability of ZMYM2 protein, the effect of which was weakened by RAD18 knockdown. UBE2B overexpression significantly enhanced the growth of xenograft tumors derived from CAOV4 cells. ZMYM2 knockdown remarkedly suppressed tumor growth and impaired the growth-promoting effect of UBE2B overexpression. In conclusion, this study revealed a novel regulatory effect of the UBE2B/RAD18 complex on ZMYM2 monoubiquitination and stability in ovarian cancer. Graphic Abstract

RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival

Abstract: Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis.