Editors' ChoiceCancer Immunology

Immune Regulatory Functions of Mutant p53

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Science Signaling  23 Dec 2014:
Vol. 7, Issue 357, pp. ec354
DOI: 10.1126/scisignal.aaa5332

The proteins in the p53 family can function as transcription factors that regulate the cellular response to stresses, such as DNA damage, but can also have functions in the cytosol. Because mutations that inhibit the transcriptional activity of p53 promote cancers, p53 is predominantly considered as a tumor suppressor. However, some mutations in p53 enable or alter cytosolic functions of the protein, enabling p53 to act as an oncoprotein (see Cooks and Harris). Tumor necrosis factor–α (TNF-α) is an inflammatory cytokine that can promote apoptosis of cancer cells. The protein DAB2IP (also known as AIP1) promotes JNK signaling and inhibits NF-κB signaling by TNF-α and also interacts with members of the p53 family. Di Minin et al. found that breast cancer cell lines and a pancreatic cancer cell line with individual “hotspot” missense mutations in p53 (collectively referred to as mutp53) had increased invasive behavior when cultured (i) with conditioned medium from activated mouse dendritic cells, which was blocked by adding an antibody against TNF-α or by knocking down mutp53, or (ii) in the presence of the TNF-α. Knockdown of mutp53 also increased the apoptotic response of the cancer cell lines to TNF-α. Transcriptional microarray analysis indicated that cancer cell lines in which mutp53 was knocked down had increased expression of genes encoding proteins associated with the immune response and cell migration in response to TNF-α. Conditioned medium from a TNF-α–exposed breast cancer cell line with mutp53, but not that from cells in which mutp53 was knocked down, stimulated the chemotaxis of T cells and natural killer cells. In cells exposed to TNF-α, mutp53 enhanced NF-κB signaling and repressed JNK signaling, which was determined by analyzing the expression of specific genes identified as regulated by TNF-α and mutp53 in the transcriptional array data. Multiple biochemical assays indicated that endogenous DAB2IP and mutp53, but not wild-type p53, interact in the cytosol. Silencing DAB2IP in cells in which mutp53 was knocked down enabled invasive behavior and prevented cell death in response to TNF-α. Overexpression of mutp53 inhibited the interaction between DAB2IP and ASK1, a kinase involved in the JNK pathway, suggesting that mechanistically mutp53 inhibits DAB2IP function by competing for binding with the JNK pathway component. Expression of a “decoy” DAB2IP-based peptide that could bind mutp53 reduced cytokine-induced invasive behavior of cultured cancer cells. Moreover, tumors in mice with xenografts of a mutp53-positive cancer cell lines expressing the DAB2IP decoy peptide had reduced growth and metastasis compared with tumors from the control mutp53-positive cells. In patients with triple negative breast cancer (TNBC), a gene expression signature based on a subset of the mutp53-stimulated genes from the transcriptional array data correlated with disease free survival and was predictive of survival in the subset of patients with mutp53-positive cancers. The mutp53-stimulated gene expression signature suggested that inflammatory signaling was enhanced, and analysis of patient tumor data for expression of genes associated with lymphocytes indicated that the mutp53-positive tumors may stimulate an immune response toward the tumor. Thus, mutp53 may promote oncogenesis by enhancing migration and survival of the tumor cells, but also inhibit disease progression by stimulating the immune response to the tumor.

G. Di Minin, A. Bellazzo, M. Dal Ferro, G. Chiaruttini, S. Nuzzo, S. Bicciato, S. Piazza, D. Rami, R. Bulla, R. Sommaggio, A. Rosato, G. Del Sal, L. Collavin, Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. Mol. Cell 56, 617–629 (2014). [PubMed]

T. Cooks, C. C. Harris, p53 mutations and inflammation-associated cancer are linked through TNF signaling. Mol. Cell 56, 611–612 (2014). [PubMed]

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