Abstract
The p63 gene is expressed as TAp63 from the P1 promoter and as ΔNp63 from the P2 promoter. Through alternative splicing, five TA and five ΔN isoforms (α-ε) are expressed. Isoforms α-β and δ share an identical 3' untranslated region (3'UTR) whereas isoform γ has a unique 3'UTR. Recently, we found that RBM38 RNA-binding protein is a target of p63 and RBM38 in turn regulates p63α/β expression via mRNA stability. However, it is uncertain whether 63γ has a unique biological activity and whether 63γ is regulated by RBM38. Here, we found that the levels of ΔNp63γ transcript and protein are induced upon overexpression of RBM38 but decreased by RBM38 knockdown. Conversely, we found that the levels of ΔNp63β transcript and protein are decreased by ectopic expression of RBM38 but increased by RBM38 knockdown, consistent with our previous report. Interestingly, RBM38 increases the half-life of 63γ mRNA by binding to a GU-rich element in 63γ 3'UTR. In contrast, our previous studies showed that RBM38 decreases the half-life of p63α/β mRNAs by binding to AU-/U-rich elements in their 3'UTR. We also found that knockout of 63γ in ME180 and HaCaT cells, in which ΔNp63 isoforms are predominant, inhibits cell proliferation and migration, suggesting that ΔNp63γ has a pro-growth activity. In contrast, we found that knockout of TAp63γ in MIA PaCa-2 cells, in which TAp63 isoforms are predominant, promotes cell proliferation, migration, and inhibits cellular senescence. Taken together, we conclude that ΔNp63γ has an oncogenic potential whereas TA63γ is a tumor suppressor.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 78327-78339 |
| Number of pages | 13 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 45 |
| DOIs | |
| State | Published - 2017 |
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Keywords
- MRNA stability
- P63
- P63γ
- RBM38
- RNA binding protein
ASJC Scopus subject areas
- Oncology
Cite this
TAp63γ and ΔNp63γ are regulated by RBM38 via mRNA stability and have an opposing function in growth suppression. / Yan, Wensheng; Zhang, Yanhong; Chen, Xinbin.
In: Oncotarget, Vol. 8, No. 45, 2017, p. 78327-78339.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TAp63γ and ΔNp63γ are regulated by RBM38 via mRNA stability and have an opposing function in growth suppression
AU - Yan, Wensheng
AU - Zhang, Yanhong
AU - Chen, Xinbin
PY - 2017
Y1 - 2017
N2 - The p63 gene is expressed as TAp63 from the P1 promoter and as ΔNp63 from the P2 promoter. Through alternative splicing, five TA and five ΔN isoforms (α-ε) are expressed. Isoforms α-β and δ share an identical 3' untranslated region (3'UTR) whereas isoform γ has a unique 3'UTR. Recently, we found that RBM38 RNA-binding protein is a target of p63 and RBM38 in turn regulates p63α/β expression via mRNA stability. However, it is uncertain whether 63γ has a unique biological activity and whether 63γ is regulated by RBM38. Here, we found that the levels of ΔNp63γ transcript and protein are induced upon overexpression of RBM38 but decreased by RBM38 knockdown. Conversely, we found that the levels of ΔNp63β transcript and protein are decreased by ectopic expression of RBM38 but increased by RBM38 knockdown, consistent with our previous report. Interestingly, RBM38 increases the half-life of 63γ mRNA by binding to a GU-rich element in 63γ 3'UTR. In contrast, our previous studies showed that RBM38 decreases the half-life of p63α/β mRNAs by binding to AU-/U-rich elements in their 3'UTR. We also found that knockout of 63γ in ME180 and HaCaT cells, in which ΔNp63 isoforms are predominant, inhibits cell proliferation and migration, suggesting that ΔNp63γ has a pro-growth activity. In contrast, we found that knockout of TAp63γ in MIA PaCa-2 cells, in which TAp63 isoforms are predominant, promotes cell proliferation, migration, and inhibits cellular senescence. Taken together, we conclude that ΔNp63γ has an oncogenic potential whereas TA63γ is a tumor suppressor.
AB - The p63 gene is expressed as TAp63 from the P1 promoter and as ΔNp63 from the P2 promoter. Through alternative splicing, five TA and five ΔN isoforms (α-ε) are expressed. Isoforms α-β and δ share an identical 3' untranslated region (3'UTR) whereas isoform γ has a unique 3'UTR. Recently, we found that RBM38 RNA-binding protein is a target of p63 and RBM38 in turn regulates p63α/β expression via mRNA stability. However, it is uncertain whether 63γ has a unique biological activity and whether 63γ is regulated by RBM38. Here, we found that the levels of ΔNp63γ transcript and protein are induced upon overexpression of RBM38 but decreased by RBM38 knockdown. Conversely, we found that the levels of ΔNp63β transcript and protein are decreased by ectopic expression of RBM38 but increased by RBM38 knockdown, consistent with our previous report. Interestingly, RBM38 increases the half-life of 63γ mRNA by binding to a GU-rich element in 63γ 3'UTR. In contrast, our previous studies showed that RBM38 decreases the half-life of p63α/β mRNAs by binding to AU-/U-rich elements in their 3'UTR. We also found that knockout of 63γ in ME180 and HaCaT cells, in which ΔNp63 isoforms are predominant, inhibits cell proliferation and migration, suggesting that ΔNp63γ has a pro-growth activity. In contrast, we found that knockout of TAp63γ in MIA PaCa-2 cells, in which TAp63 isoforms are predominant, promotes cell proliferation, migration, and inhibits cellular senescence. Taken together, we conclude that ΔNp63γ has an oncogenic potential whereas TA63γ is a tumor suppressor.
KW - MRNA stability
KW - P63
KW - P63γ
KW - RBM38
KW - RNA binding protein
UR - http://www.scopus.com/inward/record.url?scp=85029184648&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029184648&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.18463
DO - 10.18632/oncotarget.18463
M3 - Article
AN - SCOPUS:85029184648
VL - 8
SP - 78327
EP - 78339
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 45
ER -