Identification of early pregnancy factor as chaperonin 10: implications for understanding its role

Abstract

Early pregnancy factor (EPF) is a secreted substance with growth regulatory and immunomodulatory properties. It is required for successful establishment of pregnancy and for proliferation of both normal and neoplastic cells, in vivo and in vitro. The rosette inhibition test was used as a bioassay, and the appearance of EPF in serum in the very early stages of pregnancy (in mice, within 4-6 h of mating) was first described two decades ago. However, because of the difficulty of this bioassay and the paucity of EPF in biological materials, the primary structure of the molecule has been identified only recently. Seventy per cent of the amino acid sequence of EPF derived from human platelets was determined. With the exception of a single residue, this was identical to the sequence of rat mitochondrial chaperonin 10 (cpn10). Cpn10 is a heat shock protein that functions as a molecular chaperone. It binds to and stabilizes cpn60 and, in concert, these molecules mediate protein folding in mitochondria, chloroplasts and bacteria. Characterizing EPF as an extracellular form of cpn10 raises unprecedented questions about the mechanism of action. It may be that, as a molecular chaperone in the extracellular compartment, EPF can functionally modify other proteins, serving as a regulator of regulators.

Recombinant EPF/chaperonin 10 promotes the survival of O4-positive pro-oligodendrocytes prepared from neonatal rat brain

“…Both recombinant cpn 10 molecules showed similar antibody binding characteristics in an ELISA and, within the semi-quantitative limits of the EPF bioassay (Cavanagh 1996), were equally potent as EPF (data not shown). Initial experiments on mixed glial cultures (50% oligodendrocytes and 50% microglia), as determined by immunohistochemistry, indicated that EPF/cpn 10 was a survival factor for these cells, using trypan blue exclusion to measure cell viability.…”

“…Early pregnancy factor (EPF) is a molecule that is present, from soon after conception, in the sera of all pregnant mammals that have been tested (Morton et al 1992;Cavanagh 1996;Cavanagh 1997); EPF has immunomodulatory properties and growth factor properties (Morton et al 1982;Morton 1998). EPF was found to be homologous to cpn 10 (Cavanagh and Morton 1994).…”

The Unfolding Story of the Chaperonins

“…In addition to surface expression there is evidence for secretion of cpos froID luammalian cells. Thus, hunlan cpn lOis thought to be the sanle Inolecule as early pregnancy factor, which is found in the SerUITI of pregnant WOIllen (Cavanagh, 1996). In addition, human astrocytes secrete a potent allli-apoptotic cpn 60-Hke molecule (Brennenlan and Gozes.…”

“…Pregnancy and cancer are, perhaps, the Inost dramalic natural exanlples of nlalnl11alian cell growth4 Chaperonins are implicated as growth regulators in both4 Early pregnancy factor which has been identified as cpo 10, is required for the successful establishment of pregnancy and for the proliferation of both normal and neoplastic cells (Cavanagh, 1996). .…”

“…TillS review focuses on recent scientific advances in the GraE subfamily which contains two major proteins, cpn 10 and cpn 60 (Gupta, 1996); also known as GraES and GroEL (in Escherichia coli) (Georgopoulos et al, 1972), heat shock protein 10 and 58/60/65 (McMullin and Hallberg, 1988;Gupta, 1995), 10/60/65 kDa antigen (Shinnick et al, J988;Baird et al, 1989;Hoffman et al, 1990), early pregnancy factor (Cavanagh, 1996) and PI (lindalet al, 1989). The structural and folding aspects of the cpns have recently been cOluprehensively reviewed (Bukau and Horwich, 1998) and this article will concentrate on the non-folding functions of these proteins.…”