Cereblon

Cereblon

Cereblon (CRBN) is a protein encoded by the CRBN gene in humans. It is a crucial component of the E3 ubiquitin ligase complex, which plays a significant role in protein homeostasis by targeting specific proteins for degradation via the ubiquitin-proteasome system. Cereblon has gained considerable attention in the field of pharmacology due to its role as a primary target of the immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide.

Structure

Cereblon is a 442 amino acid protein that contains a Lon protease domain, which is thought to be involved in its interaction with other proteins. The protein is highly conserved across species, indicating its essential biological functions.

Function

Cereblon functions as a substrate receptor in the CRL4 (Cullin-RING Ligase 4) E3 ubiquitin ligase complex. This complex is responsible for the ubiquitination and subsequent proteasomal degradation of target proteins. Cereblon specifically binds to certain substrates, marking them for degradation. This process is crucial for regulating protein levels within the cell and maintaining cellular homeostasis.

Role in Drug Action

Cereblon is best known for its interaction with thalidomide and its analogs, lenalidomide and pomalidomide. These drugs bind to cereblon, altering its substrate specificity and leading to the degradation of specific transcription factors such as Ikaros and Aiolos. This degradation is believed to contribute to the drugs' therapeutic effects in multiple myeloma and other hematological malignancies.

Thalidomide, initially used as a sedative and anti-nausea medication, was infamously withdrawn from the market due to its teratogenic effects, which were later linked to its interaction with cereblon. The discovery of cereblon's role in thalidomide's mechanism of action has led to a better understanding of its effects and the development of safer analogs.

Clinical Significance

The modulation of cereblon activity by IMiDs has therapeutic implications in cancer treatment, particularly in multiple myeloma. By promoting the degradation of oncogenic transcription factors, these drugs can inhibit cancer cell proliferation and induce apoptosis. Additionally, cereblon has been implicated in various cellular processes, including limb development, neural tube formation, and immune response regulation.

Research Directions

Ongoing research is focused on understanding the full range of cereblon's substrates and its broader role in cellular physiology. There is also interest in developing new drugs that can modulate cereblon activity with greater specificity and fewer side effects.

Also see

• Thalidomide
• Lenalidomide
• Ubiquitin-proteasome system
• Multiple myeloma
• E3 ubiquitin ligase

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