Alpha-fetoprotein (AFP), known largely as a growth-promoting agent, possesses a growth-inhibitory motif recently identified as an occult epitopic segment in the third domain. The present study reviews the multiple biological activities of this AFP-derived peptide segment termed the Growth Inhibitory Peptide (GIP), which is a 34-amino acid fragment taken directly from the full-length 590 amino acid molecule. The GIP segment has been chemically synthesized, purified, characterized, and subjected to a variety of bioassays. The GIP has a proven record of growth suppression in both fetal and tumor cells, but not in normal adult cells. Even though the mechanism of action has not been completely elucidated, GIP participates in various biological activities such as endocytosis, angiogenesis, and cytoskeleton-induced/cell shape changes. In this review, a survey of the functional roles of the GIP is presented which encompasses multiple organizational levels of GIP involvement, including the 1) organism, 2) organ, 3) tissue, 4) cell, 5) plasma membrane, 6) cytoplasm, and 7) the nucleus. At the cell membrane interface, the actions of GIP are discussed concerning cell aggregation, agglutination, adhesion, and migration in light of GIP serving as a possible decoy ligand and/or soluble receptor. Regarding cytosolic activities, GIP has been reported to inhibit various cytoplasmic enzyme activities, modulate apoptotic events, and regulate cytoplasmic signal transduction (MAP kinase) cascades. Concerning the nuclear compartment, GIP is capable of complexing with the estrogen receptor and binding estradiol, but does not affect estradiol-induced estrogen receptor transcription. In overview, efforts were made to review the multiple biological activities reported for GIP in order to prioritize likely physiological activities and present an updated consensus of functional roles for this AFP-derived peptide.

The (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.

Both insulin and estrogen are well recognized as growth-promoting substances at physiological concentrations, but they function as teratogens at high doses. Both agents can affect alterations in fetal and maternal serum human α-fetoprotein (HAFP) levels during pregnancy. In the present study, we have employed animal models of both insulin and estrogen fetotoxicity and teratogenicity in order to study the growth-regulatory properties of HAFP and its derived peptides (HAFP/PEP). We report here the effects of HAFP/PEP on fetotoxicity, congenital malformations, and growth retardation in developing chick and murine fetuses. In the insulin model, HAFP/PEP were effective in reducing both fetal mortality and anatomic anomalies, with the result that growth-retarded fetuses were produced. With HAFP/PEP treatment, fetal demise was reduced by as much as 73 and 63% in murine and chick fetuses, respectively, while fetal anomalies were diminished by 50% during chick development. Genebank searches of identity/similarity in a HAFP/PEP fragment identified matches with a number of proteins associated with glucose, pH, ionic, osmotic, and oxidative stresses, and with heat shock, in addition to stress proteins related to protein folding/unfolding processes. It was proposed that the peptide segment on HAFP may represent a topographic ‘hotspot’, sensitive to stress/shock conditions, which exhibits a propensity for conformational alteration in the tertiary structure of the fetal protein.

Hurricane Rita struck the coast of southwest Louisiana in September 2005. The storm generated an enormous tidal surge of approximately four meters in height that inundated many thousands of acres of the coastal marsh with full strength seawater. The initial surge resulted in the deaths of a number of alligators and severely stressed those who survived. In addition, a prolonged drought (the lowest rainfall in 111 years of recorded weather data) following the hurricane resulted in highly saline conditions that persisted in the marsh for several months. We had the opportunity to collect 11 blood samples from alligators located on Holly Beach less than a month after the hurricane, but were unable to collect samples from alligators on Rockefeller Wildlife Refuge until February 2006. Conditions at Rockefeller Refuge did not permit systematic sampling, but a total of 201 samples were collected on the refuge up through August 2006. The blood samples were analyzed for sodium, potassium, chloride, osmolality, and corticosterone. Blood samples from alligators sampled on Holly Beach in October 2005, showed a marked elevation in plasma osmolality, sodium, chloride, potassium, corticosterone, and an elevated heterophil/lymphocyte ratio. Blood samples from alligators on Rockefeller Refuge showed increasing levels of corticosterone as the drought persisted and elevated osmolality and electrolytes. After substantial rainfall in July and August, these indices of osmotic stress returned to within normal limits.

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