Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration.

@article{Yeudall2012GainoffunctionMP,
  title={Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration.},
  author={William Andrew Yeudall and Catherine A. Vaughan and Hiroshi Miyazaki and Mahesh Ramamoorthy and Miyoung Choi and Christopher G Chapman and Huixin Wang and Elena Black and Anna Bulysheva and Swati Palit Deb and Brad Windle and Sumitra Deb},
  journal={Carcinogenesis},
  year={2012},
  volume={33 2},
  pages={
          442-51
        }
}
The role of dominant transforming p53 in carcinogenesis is poorly understood. Our previous data suggested that aberrant p53 proteins can enhance tumorigenesis and metastasis. Here, we examined potential mechanisms through which gain-of-function (GOF) p53 proteins can induce motility. Cells expressing GOF p53 -R175H, -R273H and -D281G showed enhanced migration, which was reversed by RNA interference (RNAi) or transactivation-deficient mutants. In cells with engineered or endogenous p53 mutants… 

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Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

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References

SHOWING 1-10 OF 80 REFERENCES

Tumor-Derived p53 Mutants Induce NF-κB2 Gene Expression

One possible pathway through which mutants of p53 may induce loss of drug sensitivity is via the NF-κB2 pathway, whose overexpression in H1299 cells also leads to chemoresistance.

Tumor-Derived p 53 Mutants Induce NF-B 2 Gene Expression

One possible pathway through which mutants of p53 may induce loss of drug sensitivity is via the NFB2 pathway, whose overexpression in H1299 cells also leads to chemoresistance.

The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis

The identification of ID4 as a transcriptional target of gain-of-function p53 mutants R175H, R273H and R280K highlights the transcriptional axis mutant p53, E2F1 and ID 4 as a still undefined molecular mechanism contributing to tumor neo-angiogenesis.

p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts.

It is reported that p53 can suppress the production of the chemokine SDF-1 in cultured fibroblasts of both human and mouse origin, suggesting that the ability of p53 to suppress stromal S DF-1 production may be an important mechanism whereby it does its non-cell-autonomous tumor suppressing function.

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

It is demonstrated that wild type but not the dominant-negative mutant (V143A) or cancer-specific mutants (R175H or R280K) of p53 repress CXCR4 expression, and proposed that p53 rescue drugs either alone or in combination with chemotherapeutic drugs may be effective in reducing CX CR4-mediated metastasis.

Down-regulation of CXCL5 inhibits squamous carcinogenesis.

It is suggested that CXCL5 production contributes to both enhanced proliferation and invasion of squamous cell carcinomas and that targeting of chemokine pathways may represent a potential therapeutic modality for these lesions.

Modulation of Gene Expression by Tumor-Derived p53 Mutants

It is shown that the increased growth rate imparted by Mutant p53 in H1299 cells requires the transactivation function of mutant p53, and constitutive expression of three common p53 mutants in H 1299 human lung carcinoma cells evokes regulation of a common set of genes, a significant number of which are involved in cell growth regulation.

Modulation of Gene Expression by Tumor-Derived p 53 Mutants

It is shown that the increased growth rate imparted by mutant p53 in H1299 cells requires the transactivation function of mutant p43, and constitutive expression of three common p53 mutants in H 1299 human lung carcinoma cells evokes regulation of a common set of genes, a significant number of which are involved in cell growth regulation.

A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis

...