Short introduction into current research

This site gives an overview of our current research field.

Research is focused on the elucidation of the structure and function of the COP9 signalosome (CSN) and its role in the ubiquitin proteasome system (UPS) and during the differentiation of preadipocytes to adipocytes (adipogenesis). 

The CSN possesses an intrinsic metalloprotease activity localized to CSN5 that removes the ubiquitin-like protein Nedd8 from cullins. Cullins are scaffolding components of CRLs (cullin-RING ubiquitin ligases) (see Figure), the most important family of ubiquitin ligases in eukaryotic cells. CSN-mediated deneddylation of cullins inactivates CRLs and at the same time allows reassembly of CRLs. A major aim of our division is the investigation of the biological function of CSN-mediated deneddylation and its role during adipogenesis.

The CSN is associated with kinases, which phosphorylate cellular regulators such as c-Jun, p27Kip, β-catenin and p53 influencing their ubiquitination and subsequent degradation. Phosphorylation of c-Jun stabilizes the transcription factor toward the UPS. In contrast, CSN-mediated phosphorylation of p53 targets the tumor suppressor to degradation by the 26S proteasome. Inhibitors of CSN-associated kinases such as curcumin and curcumin-like substances destabilize c-Jun and increase p53 levels, which reduces tumor angiogenesis and is already applied in tumor therapy. In addition, curcumin and curcumin-like substances block adipogenesis.

The CSN is associated with the ubiquitin-specific enzyme 15 (USP15), which belongs to the family of deubiquitinating enzymes. USP15 protects components of cullin-RING ubiquitin ligases (CRLs) from autoubiquitination and degradation (see Figure). A major aim of our group is the elucidation of USP15 biological function.

The CRL1-CSN superkomplex

The CRL1 obtains activated Ub from an E2 and transfers the Ub to its substrate. The substrate specifically binds to a specific F-box protein and is polyubiquitinated and subsequently degraded by the 26S proteasome. In the absence of a substrate the CSN deneddylates and inactivates the CRL1. This protects F-box proteins and perhaps other CRL components from autoubiquitination. In addition, the associated DUB USP15 protects Rbx1 from ubiquitination and degradation.

Research in collaboration with the Clinic

The role of the COP9 signalosome in tumor angiogenesis and in adipogenesis

Previous and current research:

  • The CSN as a therapeutic target: Role of the CSN in tumor angiogenesis.
  • Curcumin, piceatannol, resveratrol and emodin suppress CSN-mediated phosphorylation and the VEGF production in tumor cells.
  • Curcumin, piceatannol, resveratrol and emodin inhibit the VEGF production by preadipocytes and block adipogenesis.
  • The CSN is essential for adipogenesis.

Future projects and goals:

  • The impact of Mitomycin C on the phosphorylation of the CSN in colon tumor cells.
  • The influence of the CSN on regulatory proteins during adipocyte differentiation.
  • Studies on the role of CSN-mediated deneddylation and deubiquitination in renal tumor cells.

Basic research

Structure and function of the COP9 signalosome

Previous and current research:

  • Studies on the architecture of the CSN in collaboration with the MPI Martinsried led
  • to a 3D structure of the CSN based on cryo-electron microscopy.
  • Studies on the coordinated CSN subunit biogenesis revealed a role of miRNAs of the let-7 family.
  • Elucidation of the biological function of CSN-mediated deneddylation.
  • Investigation of the biological function of USP15 by establishing and characterizing
  • a Usp15 knockout mouse.

Future projects and goals:

  • - Studies on the role of the CSN-CRL module in urological tumors.
  • - Characterization of the Usp15 knockout mouse.
  • - Investigation of CSN function in adipogenesis.
  • - Characterization of CSN variants and their roles in adipogenesis.

Group leader

Prof. Dr. Wolfgang Dubiel
Group leader
t: +49 30 450 522 305