Mutant p53 Reprograms TNF Signaling in Cancer Cells through Interaction with the Tumor Suppressor DAB2IP

Minin, Giulio Di; Bellazzo, Arianna; Ferro, Marco Dal; Chiaruttini, Giulia; Nuzzo, Simona; Bicciato, Silvio; Piazza, Silvano; Rami, Damiano; Bulla, Roberta; Sommaggio, Roberta; Rosato, Antonio; Sal, Giannino Del; Collavin, Licio

doi:10.1016/j.molcel.2014.10.013

Cited by 139 publications

(133 citation statements)

References 47 publications

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“…This model is well characterized in endothelial cells, but is conserved in other cell types, including cancer cells. 15,18 In TNF-treated cells, DAB2IP can likewise support ASK1-JNK activation by the pro-apoptotic kinase Homeodomain-interacting protein kinase 1 (HIPK1). 19 Notably, DAB2IP also mediates ASK1-JNK activation upon endoplasmic reticulum (ER) stress (Figure 4a).…”

Section: Dab2ip: a Complex Gene Encoding A Negative Modulator Of Multmentioning

confidence: 99%

“…2,18,34,55 For instance, TNFα induces invasion in DAB2IP-inactivated breast cancer cells, triggering upregulation of a subset of NF-κB and ASK1/JNK target genes enriched in matrix-remodeling enzymes and chemokines. Intriguingly, such response can also recruit cytotoxic immune cells, potentially affecting tumor progression and prognosis.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

“…Intriguingly, such response can also recruit cytotoxic immune cells, potentially affecting tumor progression and prognosis. 18 Various lines of evidence correlate Ras activation in cancer cells with a compromised host immune response and recruitment of suppressive regulatory T cells; 9 in this perspective, loss of DAB2IP-dependent RAS-GAP activity may favor tumor escape from interactions. DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

“…We found that breast cancer cells expressing mutp53 undergo a pro-oncogenic response to inflammatory cytokines, in particular TNFα. 18 Mechanistically, by binding DAB2IP mutp53 sustains TNF-induced activation of NF-κB, counteracting the pro-apoptotic ASK1/JNK branch of the pathway. This results in a transcriptional program that promotes cell invasion and protects from cell death.…”

Section: Transcriptional Silencing By Promoter Methylationmentioning

confidence: 99%

“…Of note, expression of a decoy protein capable of interfering with DAB2IP-mutp53 interaction reduced tumor growth and metastasis in a mouse xenograft model. 18 It is plausible that the mutp53-DAB2IP interaction has a broader impact in cancer progression, affecting the cancer cell's response to additional extrinsic inputs.…”

Section: Transcriptional Silencing By Promoter Methylationmentioning

confidence: 99%

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Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

2016

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One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

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Section: Dab2ip: a Complex Gene Encoding A Negative Modulator Of Multmentioning

confidence: 99%

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

Section: Transcriptional Silencing By Promoter Methylationmentioning

confidence: 99%

Section: Transcriptional Silencing By Promoter Methylationmentioning

confidence: 99%

See 3 more Smart Citations

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

2016

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Prognostic Implications of EGFR, p53, p16, Cyclin D1, and Bcl‐2 in Head and Neck Squamous Cell Carcinoma (HNSCC)

Deliu

Shergill

Meier

et al. 2020

Precision Medicine in Oncology

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Inhibiting the IRE1α Axis of the Unfolded Protein Response Enhances the Antitumor Effect of AZD1775 in TP53 Mutant Ovarian Cancer

et al. 2022

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Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA-like ER kinase (PERK) and inositol-required enzyme 1𝜶 (IRE1𝜶) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF-𝜿B mediated senescence-associated secretory phenotype. Upon AZD1775 treatment, activated PERK promotes apoptotic signaling via C/EBP-homologous protein (CHOP), while IRE1𝜶-induced splicing of XBP1 (XBP1s) maintains cell survival by repressing apoptosis. This leads to an encouraging synergistic antitumor effect of combining AZD1775 and an IRE1𝜶 inhibitor MKC8866 in multiple cell lines and preclinical models of ovarian cancers. Taken together, the data reveal an important dual role of the UPR signaling network in mtTP53 ovarian cancer models in response to AZD1775 and suggest that inhibition of the IRE1𝜶-XBP1s pathway may enhance the efficacy of AZD1775 in the clinics.

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Mutant p53 Reprograms TNF Signaling in Cancer Cells through Interaction with the Tumor Suppressor DAB2IP

Cited by 139 publications

References 47 publications

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Prognostic Implications of EGFR, p53, p16, Cyclin D1, and Bcl‐2 in Head and Neck Squamous Cell Carcinoma (HNSCC)

Inhibiting the IRE1α Axis of the Unfolded Protein Response Enhances the Antitumor Effect of AZD1775 in TP53 Mutant Ovarian Cancer

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