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Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein
Yanjie Chen1, Takayuki Fujita, Di Zhang
1Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Abstract:
Tumor suppressor protein p53, our most critical defense against tumorigenesis, can be made powerless by mechanisms such as mutations and inhibitors. Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is up-regulated in many human malignancies. However, the exact mechanism by which fortilin exerts its anti-apoptotic activity remains unknown. Here we present significant insight. Fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. In addition, fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double point mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumor in athymic mice. Our results suggest that fortilin is a novel p53-interacting molecule and p53 inhibitor and that it is a logical molecular target in cancer therapy.
Insights
Fortilin, a protein found in many cancers, inhibits the tumor suppressor p53 by blocking its ability to trigger cell death. This interaction promotes tumor growth, suggesting fortilin as a cancer therapy target.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- The tumor suppressor protein p53 is crucial in preventing cancer but can be inactivated.
- Fortilin, a protein upregulated in malignancies, has anti-apoptotic activity, but its mechanism is unclear.
- Understanding fortilin's interaction with p53 is vital for cancer therapy development.
Purpose of the Study:
- To elucidate the mechanism by which fortilin exerts its anti-apoptotic activity.
- To investigate the interaction between fortilin and tumor suppressor p53.
- To determine the therapeutic potential of targeting fortilin in cancer.
Main Methods:
- Investigated the binding of fortilin to the DNA binding domain of p53.
- Assessed the effect of fortilin on p53-induced transcriptional activation of the Bax gene.
- Evaluated p53-dependent apoptosis in cells expressing fortilin and its mutants.
- Observed tumor formation in athymic mice with wild-type p53 and fortilin expression.
Main Results:
- Fortilin specifically binds to the DNA binding domain of p53.
- Fortilin inhibits p53-induced transcriptional activation of Bax.
- Fortilin blocks p53-dependent apoptosis, unlike a non-binding mutant.
- Cells with fortilin and wild-type p53 showed impaired Bax induction and apoptosis, leading to larger tumors in mice.
Conclusions:
- Fortilin acts as a novel p53-interacting molecule and inhibitor.
- Fortilin's inhibition of p53 contributes to tumorigenesis.
- Fortilin represents a promising molecular target for cancer therapy.
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