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RhoB is dispensable for mouse development, but it modifies susceptibility to tumor formation as well as cell adhesion
Abstract:
RhoB is an endosomal small GTPase that is implicated in the response to growth factors, genotoxic stress, and farnesyltransferase inhibitors. To gain insight into its physiological functions we examined the consequences of homozygous gene deletion in the mouse. Loss of RhoB did not adversely affect mouse development, fertility, or wound healing. However, embryo fibroblasts cultured in vitro exhibited a defect in motility, suggesting that RhoB has a role in this process that is conditional on cell stress. Neoplastic transformation by adenovirus E1A and mutant Ras yielded differences in cell attachment and spreading that were not apparent in primary cells. In addition, transformed -/- cells displayed altered actin and proliferative responses to transforming growth factor beta. A negative modifier role in transformation was suggested by the increased susceptibility of -/- mice to 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis and by the increased efficiency of intraperitoneal tumor formation by -/- cells. Our findings suggest that RhoB is a negative regulator of integrin and growth factor signals that are involved in neoplastic transformation and possibly other stress or disease states.
Insights
The small GTPase RhoB acts as a negative regulator in neoplastic transformation. Its absence in mice increased susceptibility to skin cancer and tumor formation, suggesting a crucial role in controlling cell growth signals.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- RhoB is an endosomal small GTPase involved in cellular responses.
- Its precise physiological functions, particularly in stress and disease, remain incompletely understood.
Purpose of the Study:
- To investigate the physiological roles of RhoB by examining the effects of its homozygous gene deletion in mice.
- To elucidate RhoB's function in neoplastic transformation and its regulation of cellular signaling pathways.
Main Methods:
- Generated and analyzed RhoB-deficient (RhoB-/-) mice and their corresponding embryo fibroblasts.
- Assessed cellular phenotypes including motility, attachment, spreading, and proliferation.
- Evaluated neoplastic transformation using adenovirus E1A and mutant Ras.
- Investigated responses to transforming growth factor beta (TGF-β).
- Examined in vivo carcinogenesis and tumor formation models.
Main Results:
- RhoB deficiency did not impact mouse development, fertility, or wound healing.
- RhoB-/- embryo fibroblasts showed impaired motility under stress conditions.
- Transformed RhoB-/- cells exhibited altered attachment, spreading, and actin dynamics.
- RhoB-/- cells displayed modified proliferative responses to TGF-β.
- RhoB-/- mice showed increased susceptibility to skin carcinogenesis.
- RhoB-/- cells formed tumors more efficiently in vivo.
Conclusions:
- RhoB functions as a negative regulator of neoplastic transformation.
- It modulates integrin and growth factor signaling pathways critical for cell growth and cancer.
- RhoB plays a conditional role in cell motility and stress responses.