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Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma
S C Cleverley1, P S Costello, S W Henning
1Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Abstract:
In vitro studies in model cell lines have implicated the GTPase Rho in the control of diverse cellular responses including the control of the actin cytoskeleton and the regulation of cell cycle progression. It is also reported that the transformation of fibroblasts via oncogenic Ras requires intact Rho signalling. An invaluable tool used to investigate Rho function is the bacterial toxin C3 transferase derived from Clostridium botulinum. C3 transferase ribosylates Rho in its effector domain thereby abolishing interaction with downstream effectors. We have previously reported the use of C3 transferase under the control of the thymocyte specific lck promoter to explore the role of Rho in T cell biology. Strikingly, lck-C3 mice develop aggressive malignant thymic lymphoblastic lymphomas between 4 and 8 months of age. These studies reveal that loss of Rho function is associated with prediposition to lymphoid cell transformation. Inhibition of Rho function has been suggested as a therapeutic strategy for treatment of Ras-transformed tumours. The development of lymphomas in mice devoid of functional Rho in their T cell compartment shows that such a strategy would need to be used with caution.
Insights
Loss of Rho GTPase function in T cells leads to aggressive lymphomas, suggesting caution is needed when considering Rho inhibition as a cancer therapy.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- GTPase Rho regulates cellular processes like actin cytoskeleton dynamics and cell cycle progression.
- Rho signaling is crucial for Ras-mediated fibroblast transformation.
- C3 transferase from Clostridium botulinum inhibits Rho function by ribosylation.
Purpose of the Study:
- To investigate the role of Rho in T cell biology.
- To explore the consequences of Rho loss of function in T cells.
Main Methods:
- Utilized transgenic mice expressing C3 transferase under the lck promoter (lck-C3 mice).
- Studied T cell development and lymphoid cell transformation in lck-C3 mice.
Main Results:
- lck-C3 mice developed aggressive malignant thymic lymphoblastic lymphomas between 4 and 8 months of age.
- Loss of Rho function predisposes lymphoid cells to transformation.
- Rho inhibition may be a therapeutic strategy for Ras-transformed tumors, but requires caution.
Conclusions:
- Rho GTPase is essential for preventing lymphoid cell transformation.
- Targeting Rho function therapeutically needs careful consideration due to potential oncogenic effects in T cells.