Crosstalk between TAp73 and TGF-β in fibroblast regulates iNOS expression and Nrf2-dependent gene transcription

Area of Science:

• Molecular Biology
• Cellular Biology
• Immunology

Background:

• Inducible nitric oxide synthase (iNOS) has dual roles in anti-tumor/anti-microbial effects and promoting carcinogenesis.
• The tumor suppressor p53 normally downregulates iNOS by repressing NOS2 gene induction.
• The p53 homologue TAp73's role in iNOS regulation is investigated.

Purpose of the Study:

• To elucidate the function of TAp73 in controlling inducible nitric oxide synthase (iNOS) expression.
• To understand the interplay between TAp73, TGF-β, and iNOS in cellular responses.
• To assess the impact of TAp73 deficiency on NO-mediated adaptive responses and antimicrobial activity.

Main Methods:

• Comparison of iNOS induction in immortalized fibroblasts from TAp73 knockout (^-/-) and wild-type (^+/+) mice.
• Analysis of NOS2 transcript levels and iNOS protein stability.
• Assessment of TGF-β signaling pathway involvement using inhibitors and exogenous TGF-β1.
• Evaluation of NO-dependent induction of Nrf2 and HIF-1 target genes.
• Testing the antimicrobial efficacy of NO against Trypanosoma musculi.

Main Results:

• TAp73^-/- fibroblasts exhibited upregulated iNOS induction due to increased NOS2 transcripts and protein stability.
• TAp73 deficiency enhanced NO production, leading to stronger induction of Nrf2 and HIF-1 target genes.
• The antimicrobial activity of NO against Trypanosoma musculi was enhanced in TAp73^-/- cells.
• TAp73 and TGF-β signaling pathways cooperate to suppress iNOS expression.

Conclusions:

• Tumor suppressive TAp73 isoforms collaborate with TGF-β to regulate iNOS expression.
• TAp73 influences NO-dependent adaptive responses to nitrosative stress.
• TAp73 plays a role in controlling pathogen proliferation through NO modulation.