TAp63γ and ΔNp63γ are regulated by RBM38 via mRNA stability and have an opposing function in growth suppression

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 p63γ has a unique biological activity and whether p63γ 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 p63γ mRNA by binding to a GU-rich element in p63γ 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 p63γ 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 TAp63γ is a tumor suppressor.

The foggy world(s) of p63 isoform regulation in normal cells and cancer

“…Clinically, p63 has value in identifying malignancy and for tumour classification, and isoform‐specific ΔNp63 antibodies are superior to assessing total p63 in many situations (reviewed in ref 249). In addition, although not well studied in clinical material, TAp63 provides prognostic information [15,18,249–251] and requires more study in lymphomas and lymphocytes (including tumour‐infiltrating lymphocytes) to understand its prognostic impact and opportunities for therapy. Advances in understanding p63 isoforms and their regulation will inevitably lead to new diagnostic, prognostic and therapeutic opportunities for cancer and other pathological conditions.…”

Serine 195 phosphorylation in the RNA-binding protein Rbm38 increases p63 expression by modulating Rbm38’s interaction with the Ago2–miR203 complex

“…We also found that Rbm38 decreases p63␣/␤ mRNA stability by binding to AU/Urich elements in their 3ЈUTR (12,13). By contrast, Rbm38 enhances p63␥ mRNA stability by binding to a GU-rich element in p63␥ 3ЈUTR, which has a sequence different from that in p63␣/␤ 3ЈUTR (14). In addition, we found that Rbm38 interacts with p53 mRNA and represses p53 translation (15).…”

“…pcDNA3 vector expressing GFP was generated as described previously (20). pcDNA3 vector expressing HA-tagged p53-R175H was generated as described previously (14). The pcDNA3 p53-R175H-3ЈUTR reporter was generated by cloning p63 3ЈUTR into pcDNA3-HA-p53-R175H downstream of p53-R175H-CDS.…”

RNA Binding Protein RNPC1 Promotes Gastric Cancer Progression via Stabilizing the Aurora Kinase B mRNA

“…The underlying mechanisms of RNPC1 in the process of tumors may be due to its stabilizing effect on mRNA of oncogenes or tumor suppressors. For example, RNPC1 can regulate biological processes by binding and stabilizing the mRNA of p21 [45], p73 [46], Hu antigen-R (HuR) [45,47] and macrophage inhibitory cytokine-1 (MIC-1) [48], Zonula occludens-1 (ZO-1) [49], PTEN [25,29] (phosphatase and tensin homolog gene on chromosome 10), estrogen receptor (ER) [43], and progesterone receptor (PR) [50] or by binding to the mRNAs of p63 [51][52][53][54], c-myc [55], murine double minute-2 (MDM2) [56],and p53 [25] and mediating the decrease in the mRNA levels. In our previous study, we de ned thatAURKB was the targeted gene of RNPC1 by RIP-Seq [29].…”