Various p53 mutant types differently regulate the Ras circuit to induce a cancer-related gene signature

Solomon, Hilla; Buganim, Yosef; Kogan-Sakin, Ira; Pomeraniec, Leslie; Assia, Yael; Madar, Shalom; Goldstein, Ido; Brosh, Ran; Kalo, Eyal; Beatus, Tsevi; Goldfinger, Naomi; Rotter, Varda

doi:10.1242/jcs.099663

Cited by 60 publications

(58 citation statements)

References 37 publications

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“…For instance, mutants R175H and H179R bind strongly to BTG2, a protein that interacts with H-Ras and represses its activity. Suppressed BTG2 consequently stimulates Ras-mediated signaling, promoting tumor cell proliferation [25]. p53 mutants R248W and R273H are capable of interacting with the nucleic acid enzyme MRE11 to inhibit the binding of MRE11-RAD50-NBS1 (MRN) complexes with DNA double-strand breaks, impairing DNA repair via homologous recombination function [26].…”

Section: Mechanisms Of Mutp53 Gofmentioning

confidence: 99%

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Li²,

Guan³

et al. 2016

Chemotherapy

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Purpose: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. Methods: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. Results: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. Conclusion: mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.

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Section: Mechanisms Of Mutp53 Gofmentioning

confidence: 99%

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Li²,

Guan³

et al. 2016

Chemotherapy

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“…Various evidences suggest that mutp53 oncogenic properties are deeply connected to tumor inflammation (Solomon et al, 2011(Solomon et al, , 2012Yeudall et al, 2012). Perhaps the most convincing is a recent study on a mouse model of inflammatory bowel disease, reporting that mutp53 amplifies and sustains the proinflammatory microenvironment, leading to an increase in the rate of transformation (Cooks et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Minin¹,

et al. 2014

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Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-κB activation while it dampens activation of ASK1/JNK by TNFα, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer.

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“…23 Furthermore, TIS21 /BTG2/Pc3 arrests proliferation of fibroblasts transduced with oncogenic Ras, and inhibits cancer gene signatures by reducing guanosine-5'-triphosphate loading to Ras. 24,25 Inhibition of cell division cycle by TIS21 /BTG2/Pc3 is regulated by inhibiting cyclin D1 26 and cyclin E/CDK4 27 expressions depending on pRB expression. Moreover, TIS21 /BTG2/Pc3 has been suggested as a pan-cell cycle regulator and cell death molecule.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

Jung

et al. 2015

Oncogene

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The mammalian homolog of Drosophila diaphanous (mDia), actin nucleator, has been known to participate in the process of invasion and metastasis of cancer cells via regulating a number of actin-related biological processes. We have previously reported that tumor suppressor TIS21(/BTG2/Pc3) (TIS21) inhibits invadopodia formation by downregulating reactive oxygen species (ROS) in MDA-MB-231 cells. We herein report that TIS21(/BTG2/Pc3) downregulates diaphanous-related formin (DRF) expression via reducing NADPH oxidase 4 (Nox4)-derived ROS generation by Akt1 activation and subsequently impairs invasion activity of the highly invasive breast cancer cells. Knockdown of Akt1 by RNA interference recovered the TIS21(/BTG2/Pc3)-inhibited F-actin remodeling and ROS generation by recovering Nox4 expression. Furthermore, Sp1-mediated Nox4 transcription was downregulated by TIS21(/BTG2/Pc3)-Akt1 signals, leading to the inhibition of cancer cell invasion via F-actin remodeling by mDia genes. To our best knowledge, this is the first study to show that TIS21(/BTG2/Pc3)-Akt1 inhibited Sp1-Nox4-ROS cascade, subsequently reducing invasion activity via inhibition of mDia family genes.

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Various p53 mutant types differently regulate the Ras circuit to induce a cancer-related gene signature

Cited by 60 publications

References 37 publications

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

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

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes

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