Review and proposed action of alpha‐fetoprotein growth inhibitory peptides as estrogen and cytoskeleton‐associated factors

Abstract

AbstractThe (H) human growth‐promoting factor, alpha‐fetoprotein (AFP), has been reported to possess a growth inhibitory motif as an occult epitope in the compactly folded circulating form of the protein. Intermediate unfolded forms of the human HAFP molecule induced by stress, shock, and high ligand concentrations have revealed the presence of an encrypted growth‐suppressive segment on the third domain of HAFP. A purified linear synthetic 34‐mer segment termed the “growth inhibitory peptide” (GIP) exhibits various oligomeric forms with complex aggregation behaviors, in which dominant trimeric forms were found to be suppressive in assays of estrogen‐induced growth. While several amino acid analogs of the cysteines of the GIP retained inhibitory activity, heavy metal binding and pre‐incubation of the peptides with a variety of cations and hormone ligands were found to influence the outcomes of growth bioassays. Smaller segments of the original 34‐mer were each found to display growth activities of their own, with the middle segment (P149b) also showing hydrophobic dye‐binding properties. Studies of amino acid sequence identity further revealed that the GIP sequences displayed identity/similarity matches to both cytoplasmic and nucleus‐cytoskeleton‐associated proteins, and experimental evidence served to support these findings. That is, the peptide was capable of modulating tubulin polymerization, cell shape, and cell‐surface aggregation phenomena reminiscent of a microtubule‐associated protein. Immunofluorescence studies further pinpointed the localization of the GIP to cytoplasmic regions of high cytoskeletal density in the cell. Because of the involvement of the GIP in experimental models of the estrogen receptor/cytoskeleton, a mechanism of action is forwarded in which the linear GIP is proposed to be a G‐coupled receptor binding ligand that is translocated across the plasma membrane via receptor‐mediated endocytosis. Thus, it was predicted that the linear GIP and possibly its peptidic segments serve as decoy ligands to cell‐surface receptors in order to gain access to the cytoplasmic compartment of the cell.