What is it about?

The tumor suppressor von Hippel Lindau, pVHL, plays a role in repressing angiogenic pathways, migration, and cell growth. We show that pVHL can repress the oncogene Mdm2, a protein that can promote angiogenesis, migration, and cell growth. This repression is mediated by blocking kinase signaling pathways that induce the Mdm2 gene and stabilize the Mdm2 protein. Thus, mutation of pVHL can lead to elevated Mdm2 to promote tumor progression.

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Why is it important?

It has been well characterized that the oncogene Mdm2 represses the tumor suppressor p53 and forms an autoregulatory feedback loop, thereby alleviating p53-mediated growth suppression after DNA damage. In growing cells, the tumor suppressor pVHL can activate p53 by blocking the pro-growth pathways that suppress the Mdm2 gene expression and protein level. Blocking this pathway restores p53 activity to impede cell growth. This work shows how the tumor suppressor pVHL can function to block an oncogene, leading to the activation of another tumor suppressor, p53.

Perspectives

Tumor suppressor mutations are hallmarks of tumor development. To maintain normal cellular activities, a dynamic interplay exists between tumor suppressors, oncogenes, and kinase signaling pathways. Our work integrates the impact of the loss of pVHL and the activation of kinase signaling pathways that lead to the induction of the Mdm2 oncogene. Mdm2 is a multifaceted protein that represses the tumor suppressor p53. This work shows a complex network of tumor suppressors that regulates cell growth, which can be overcome by inactivating one tumor suppressor.

Lindsey Mayo

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This page is a summary of: Induction of the Mdm2 gene and protein by kinase signaling pathways is repressed by the pVHL tumor suppressor, Proceedings of the National Academy of Sciences, July 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2400935121.
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