Within the last 15 years, the carboxyterminal third domain of alpha-fetoprotein (AFP-CD) has been shown to bind to various hydrophobic ligands, receptors and signaling proteins. These reports have established that AFP-CD contains several large fragments of amino acid (AA) sequences that interact with scavenger, mucin, lysophospholipid and chemokine receptors. By means of computer software designed to identify protein-to-protein interactions via specific peptide segments, the present report describes AA sequence stretches on AFP-CD that interact with both selective and non-selective ion channels. The cation channel proteins identified were the selective potassium voltage-gated (Kv) channels and the non-selective cation transient receptor potential (TRP) channels. The Kv channels encompass the KCN (potassium channels) subfamily members A, B, D, J and Q; whereas the constituents of the TRP subfamily included the canonical (C), vanilloid (V) and melastatin (M) members. Following detection of the AFP-CD of cation channel identities, the computer-derived channel localization sequences were compared to known hydrophobic and receptor interaction sites previously reported on AFP-CD. A literature search for the association of the cation channels with known fatty acid lysophospholipid, and scavenger, mucin and chemokine receptors showed positive relationships. Previous reports on the influences of experimental AFP-derived peptides on cation channel activities served to confirm and verify the present computer cation channel identifications. The Kv ion channel current (conductance) changes in the cell membrane have been reported in MCF-7 breast cancer cells which correlate with the G1 phase events of the cell cycle. During progression from the G1 to S-phase, there is a marked hyperpolarization of the cell membrane potential corresponding to an increasing intensity of the Kv current. After 7 days in culture with MCF-7 cells, an AFP-derived peptide has been shown by RNA microarray analysis to downregulate cyclin-E, SKP2, and several cation channel RNA transcripts of proteins that modulate cyclin E/Cdc2 transition from the G1 to S-phase of the cell cycle.
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