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Mutations prevent programmed cell death

December 18, 2014
Technische Universitaet Muenchen
Programmed cell death is a mechanism that causes defective and potentially harmful cells to destroy themselves. It serves a number of purposes in the body, including the prevention of malignant tumor growth. Now, researchers have discovered a previously unknown mechanism for regulating programmed cell death. They have also shown that patients with lymphoma often carry mutations in this signal pathway.

A team of scientists headed by Dr. Florian Bassermann at the III. Medizinische Klinik, TUM Klinikum rechts der Isar, has been investigating mantle cell lymphoma, a subgroup of non-Hodgkin's lymphoma, which, despite new therapies, has poor patient survival rates. "Programmed cell death no longer functions in many lymphoma cells. This causes them to multiply uncontrollably. We urgently need to find out what's going wrong in these cells in order to find new treatment therapies," explains Bassermann.

The scientists started analyzing samples of human mantle cell lymphoma in a bid to find errors in the DNA. They discovered a region that is mutated in almost 30 percent of patients. The scientists found that this region plays a key role in producing one particular enzyme, the ubiquitin ligase FBXO25. "We already knew that ubiquitin ligases are involved in breaking down proteins in cells. Now, however, we can show just how it contributes to the development of lymphoma," explains Bassermann.

Survival strategy of cancer cells

During the course of numerous experiments, the scientists were able to decode a new signal path that triggers programmed cell death. Before a cell can start destroying itself, one particular protein that keeps healthy cells alive has to be removed. The researchers discovered that the ubiquitin ligase FBXO25 marks this protein with a signal molecule which triggers the disposal process.

"If there is a defect in the ubiquitin ligase, this mechanism no longer functions. The tumor cells in question do not destroy themselves and start growing unchecked," continues Bassermann. The scientists also showed that cells with mutated FBXO25 displayed a much poorer response to chemotherapies, leaving the tumors in a much more stable condition. In a further finding, the researchers discovered other mutations in the cancer cells under investigation. In some cases, the very protein that keeps the cell alive was defective, carrying a mutation that made it resistant to destruction.

New therapies targeting ubiquitin ligase

Once this new signal path had been discovered, the scientists started working on a new therapy approach. They treated the cancer cells in such a way that they were able -- once again -- to create a functioning variant of the ubiquitin ligase. Instead of multiplying uncontrollably, the cells began destroying themselves again.

"We need to zero in on the exact defect in a tumor cell in order to adapt therapies more closely to individual types of tumors -- this is particularly relevant to the field of personalized medicine. Our findings show that this signal path for mantle cell lymphoma could offer a promising approach for new therapies," concludes Bassermann.

Story Source:

Materials provided by Technische Universitaet Muenchen. Note: Content may be edited for style and length.

Journal Reference:

  1. Ursula Baumann, Vanesa Fernández-Sáiz, Martina Rudelius, Simone Lemeer, Roland Rad, Anna-Maria Knorn, Jolanta Slawska, Katharina Engel, Irmela Jeremias, Zhoulei Li, Viktoriya Tomiatti, Anna-Lena Illert, Bianca-Sabrina Targosz, Martin Braun, Sven Perner, Michael Leitges, Wolfram Klapper, Martin Dreyling, Cornelius Miething, Georg Lenz, Andreas Rosenwald, Christian Peschel, Ulrich Keller, Bernhard Kuster, Florian Bassermann. Disruption of the PRKCD–FBXO25–HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis. Nature Medicine, 2014; 20 (12): 1401 DOI: 10.1038/nm.3740

Cite This Page:

Technische Universitaet Muenchen. "Mutations prevent programmed cell death." ScienceDaily. ScienceDaily, 18 December 2014. <>.
Technische Universitaet Muenchen. (2014, December 18). Mutations prevent programmed cell death. ScienceDaily. Retrieved December 1, 2023 from
Technische Universitaet Muenchen. "Mutations prevent programmed cell death." ScienceDaily. (accessed December 1, 2023).

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