Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin

Abstract

TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α–η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11- deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…IGF2 [632], RPPH1 [633], PRKCB (protein kinase C beta) [634], CCL5 [635], VASH2 [636], GREM1 [637], CYP11B2 [638], HIC1 [639], PCK1 [640], HSD11B2 [641], MME (membrane metalloendopeptidase) [642], FABP1 [142], MIOX (myo-inositol oxygenase) [643], ARG2 [644], PPARGC1A [645], VNN1 [646], NOX4 [647], EPHX2 [577], DDIT4 [648], SLC2A1 [649], PFKFB2 [650], CDH2 [651], SLC22A2 [294], AQP2 [652], ANGPT1 [653], KL (klotho) [654], ACE2 [655], STC1 [656], REN (renin) [608], ERRFI1 [657], ERBB4 [658], NTNG1 [659], VCAM1 [660], PTGER3 [661] and BBOX1 [662] expression levels are associated with diabetic nephropathy. IGF2 [663], IRF7 [664], PRKCB (protein kinase C beta) [665], CCL5 [666], ACTN3 [667], AMH (anti-Mullerian hormone) [668], E2F1 [669], UBE2M [670], TP73 [671], AGER (advanced glycosylation end-product specific receptor) [672], SMPD3 [118], NR2E1 [673], ANGPTL3 [674], CYP3A5 [675], PCK1 [676], LRP2...…”

maGENEgerZ: An Efficient AI-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism

“…Thirteen genes (AKT1, ARAF, CCND1, EGFR, ERBB2, ERBB3, MTOR, IGF1R, JAK2, MET, PTEN, RAF1, and STAT3) were related to EGFR tyrosine kinase inhibitor resistance (WP4806), which was reported as significant pathway associated with breast cancer [69,84]. Twelve genes (AKT1, CCND1, ERBB2, ESR1, MTOR, IRS1, JAK2, NOS3, PTEN, RAF1, STAT1, and STAT3) were linked to Leptin signaling pathway (WP2034), reported to have a key role in breast cancer tumorigenesis [85]. Nine genes (AKT1, EGFR, ERBB2, ERBB3, ESR1, MTOR, IRS1, MET, and PTEN) were linked to PI3K/AKT Signaling in Cancer (R-HSA-2219528) in which its inactivation suppressing the proliferation of breast cancer cells and thereby inducing apoptosis [86].…”