1.C.110 The Pore-forming PNC-27 Peptide of 32 aas from the p53 Tumor Suppressor Protein (PNC-27) Family
The 32 amino acid PNC-27 peptide (PPLSQETFSDLWKLLKKWKMRRNQFWVKVQRG) inserts into the membranes of tumor cells and selectively kills them, leaving normal cells unaffected. This peptide is from the Mdm-2 binding domain of the p53 protein which is selectively cytotoxic to cancer cells. The NMR structure is available (PDB# 1Q2F; 12QI-A). The p53 cellular tumor antigen, p53-TAD, is 393 aas in humans and of similar sizes in other animals (Sookraj et al. 2010). Anti-cancer tumor cell necrosis of epithelial ovarian cancer cell lines depends on high expression of the HDM-2 protein in their membranes (Thadi et al. 2020). The HDM-2 protein is highly expressed in the membranes of ovarian cancer cell lines and colocalizes with PNC-27. Thus, the association of PNC-27 with preferentially expressed membrane HDM-2 isoforms results in a model for the formation of transmembrane pores and epithelial ovarian cancer tumor cell necrosis (Thadi et al. 2020). P53 inhibition attenuates mitochondrial dysfunction and protects dopaminergic neurons from degeneration under conditions of neurodegenerative stress, and thus, p53 may be a potential target for neuroprotective therapy of poarkinson's disease (PD) (Wang et al. 2022).
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The PNC-37 (32 aas) pore-forming peptide derived from the Mdm-2 binding domain of the p53 tumor-supressor protein which is selectively cytotoxic to cancer cells. The 3-d structure is known from NMR analyses (Sookraj et al. 2010). PNC-37 binds to HDM-2 in a 1:1 stoichiometry to induce pore-formation, and the pores are lined by PNC-37 bound to HDM-2 at the membrane surface with the PNC-37 leader sequence lining the pores (Sarafraz-Yazdi et al. 2022). The interaction of the C-terminal domain of Vaccinia-Related Kinase 2A (VRK2A) with the B-cell lymphoma-extra Large (Bcl-xL) plays an anti-apoptotic role in cancer (Puja et al. 2023). P53 is a multifunctional protein implicated in the regulation of diverse cellular processes via transcription-dependent and transcription-independent mechanisms (Wang et al. 2024). Mitochondria maintain cellular function, and mitochondrial defects or impairment are primary causes of dopaminergic neuron degeneration in PD. Mitochondrial dysfunction-associated dopaminergic neuron degeneration is tightly regulated by p53 in PD pathogenesis. Neurodegenerative stress triggers p53 activation, which induces mitochondrial changes, including transmembrane permeability, reactive oxygen species production, Ca2+ overload, electron transport chain defects and other dynamic alterations, and these changes contribute to neurodegeneration and are linked closely with PD occurrence and development. P53 inhibition has been shown to attenuate mitochondrial dysfunction and protect dopaminergic neurons from degeneration under conditions of neurodegenerative stress (Wang et al. 2024).
Animals
p53 of Homo sapiens
The p53 protein of 363 aas
Animals
p53 protein of Xenopus laevis
The p53 protein of 371 aas.
Animals
p53 of Sarcophilus harrisii