Detecting the body’s reproductive hormonal brake against tissue overgrowth: micrin/SgII-70

Abstract

A new humoral factor has been detected, within a project aiming to disclose the body’s reproductive hormonal brake against tissue overgrowth, micrin (‘my-crin’). It is hypothesized that micrin braking, gonadal and hypothalamic, is lifted at puberty and wanes with age, bringing on prostatic enlargement and cancers. Factor purification has involved fractionation of ovine and bovine ovarian follicular fluid and blood plasma and serum, with evaluation via rat bioassays in vivo and in vitro. Analysis averse, the molecular effector provided a chemical conundrum. Evidence from mass spectrometry (MS) has been problematic, with spectra from MALDI-TOF, the only productive MS modality, confused by a target polypeptide exhibiting artefacts during processing, storage and MALDI set-up in terms of C-terminal truncation and water losses, together with N-terminal grand fragmentations and dimerizations (factor fragments doubled up). Evidence from chemical sequencing of amino acid (aa) residues was likewise baffling, but consistent with a spiralised depolymerisation within the Edman reaction chamber of a unitary polypeptide. Data decryption has overcome molecular intractability, supported by the results of tryptic digestion and epitope mapping using immunohistochemistry (IHC). The detected inhibitory factor is sleuthed to relate to secretogranin II (SgII), the neurosecretory prohormone, in the form of a secreted acidic 70-aa polypeptide derivative called here SgII-70 (‘sig two seventy’). The product of peptide splicing, micrin/SgII-70 is potentially an amphipathic molecular ampersand (&), with ends entwined (via salt bridging), the knotty totality compromising Edman and MALDI analyses and molecular modelling whilst conferring protease and heat resistance. The two ends of the factor are conceptualised as binding at the same time to a dimeric cellular receptor, to stoichiometric effect, providing fewer smaller cells within a counting mechanism of tissue-mass regulation. Hexapeptide mimetics simulating both ends of the hormone together have been demonstrated in different species and settings, in the cause of antiorganotrophism (tissue reduction) and reproductive modulation. Therapeutic exploitation beckons for mimetics of the body’s hormonal brake, micrin/SgII-70, in tissue overgrowth conditions such as endometriosis, PCOS, BPH and cancer, and in infertility.