Abstract
p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53R270H/− MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR+/−; p53R270H/− mice as compared with p53R270H/− mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6256-6269 |
| Number of pages | 14 |
| Journal | Oncogene |
| Volume | 38 |
| Issue number | 35 |
| DOIs | |
| State | Published - Aug 29 2019 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
Iron regulatory protein 2 is a suppressor of mutant p53 in tumorigenesis. / Zhang, Yanhong; Feng, Xiuli; Zhang, Jin; Chen, Minyi; Huang, Eric; Chen, Xinbin.
In: Oncogene, Vol. 38, No. 35, 29.08.2019, p. 6256-6269.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Iron regulatory protein 2 is a suppressor of mutant p53 in tumorigenesis
AU - Zhang, Yanhong
AU - Feng, Xiuli
AU - Zhang, Jin
AU - Chen, Minyi
AU - Huang, Eric
AU - Chen, Xinbin
PY - 2019/8/29
Y1 - 2019/8/29
N2 - p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53R270H/− MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR+/−; p53R270H/− mice as compared with p53R270H/− mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.
AB - p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53R270H/− MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR+/−; p53R270H/− mice as compared with p53R270H/− mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.
UR - http://www.scopus.com/inward/record.url?scp=85070213680&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070213680&partnerID=8YFLogxK
U2 - 10.1038/s41388-019-0876-5
DO - 10.1038/s41388-019-0876-5
M3 - Article
C2 - 31332290
AN - SCOPUS:85070213680
VL - 38
SP - 6256
EP - 6269
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 35
ER -