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Updated: Jun 23, 2026
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
Ubiquitin-mediated control of oncogene and tumor suppressor gene products
Kyoko Kitagawa1, Yojiro Kotake, Masatoshi Kitagawa
1Department of Biochemistry 1, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Abstract:
Cellular levels of products from both oncogenes and tumor suppressor genes in normal cells need to be critically regulated to avoid malignant transformation. These products are often controlled by the ubiquitin proteasome pathway, the specific degradation mechanism in the cell. E3 ubiquitin ligases polyubiquitylate their specific substrates by collaborating with E1 and E2, and then the modified substrates are degraded in the proteasome. Mdm2 targets p53 and retinoblastoma protein, two major tumor suppressor gene products, for ubiquitin-dependent degradation. SCF(Skp2) targets other tumor suppressor gene products and CDK inhibitors such as p130, Tob1, p27(Kip1), p57(Kip2), and p21(Cip1). Therefore, both E3 ligases act like oncogene products. In contrast, degradation of several oncogene products, such as Cyclin E, Notch, c-Myc, c-Jun, and c-Myb, are mediated by SCF(Fbw7). Fbw7 is often deleted or mutated in human cancers and acts like a tumor suppressor. As well as growth factor receptors and signal transduction regulators, DNA repair-related proteins are also regulated via the ubiquitin-proteasome pathway mediated by their specific E3 ligases. The stabilization of oncogene products and enhanced degradation of tumor suppressor gene products or DNA repair proteins might be associated with carcinogenesis and malignant progression, due to defects or the abnormal expression of their E3 ligases.
Insights
The ubiquitin proteasome pathway regulates oncogenes and tumor suppressors via E3 ubiquitin ligases. Dysregulation of these E3 ligases can drive cancer by altering protein stability.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Cellular regulation of oncogenes and tumor suppressor gene products is crucial for preventing malignant transformation.
- The ubiquitin proteasome pathway is a key cellular mechanism controlling protein degradation.
- E3 ubiquitin ligases play a critical role in targeting specific substrates for proteasomal degradation.
Purpose of the Study:
- To elucidate the role of E3 ubiquitin ligases in regulating tumor suppressor and oncogene products.
- To understand how the ubiquitin proteasome pathway contributes to carcinogenesis and malignant progression.
- To highlight the dual role of E3 ligases as potential oncogene or tumor suppressor products.
Main Methods:
- The study reviews the known functions of specific E3 ubiquitin ligases, including Mdm2, SCF(Skp2), and SCF(Fbw7).
- It examines the substrates targeted by these ligases, focusing on tumor suppressor proteins (p53, retinoblastoma protein) and oncogene products (Cyclin E, Notch, c-Myc).
- The research analyzes the implications of E3 ligase expression and function in the context of cancer development.
Main Results:
- Mdm2 and SCF(Skp2) target tumor suppressor gene products for degradation, acting similarly to oncogene products.
- SCF(Fbw7) mediates the degradation of oncogene products and is often deleted or mutated in cancers, functioning as a tumor suppressor.
- The ubiquitin proteasome pathway also regulates DNA repair proteins, with implications for cancer.
Conclusions:
- Defects or abnormal expression of E3 ubiquitin ligases can lead to the stabilization of oncogenic proteins and/or enhanced degradation of tumor suppressor proteins.
- These alterations in protein homeostasis mediated by E3 ligases are associated with carcinogenesis and malignant progression.
- E3 ligases are critical regulators in cancer development, acting as either oncogene or tumor suppressor-like entities depending on their targets and function.
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