Recombinant Human CREG Protein

Cellular repressor of E1A-stimulated genes (CREG) is a 25 - 35 kDa member of the CREG family of proteins. It is a secreted glycoprotein ubiquitously expressed in mammals. Human CREG is synthesized as a 220 amino acid (aa) precursor that contains a 31 aa signal sequence and a 189 aa mature chain. The mature chain contains three potential sites for N-linked glycosylation. Human CREG shares 78% aa sequence identity with mouse CREG (1, 2, 3). It antagonizes 12SE1A-mediated transcriptional activation of both adenovirus E2 and cellular heat shock protein 70 promoters (1, 3). Studies show that it inhibits E1A-mediated transformation of primary cultured rat kidney cells and promotes human embryonic carcinoma cell (NTERA-2) differentiation (1, 4). Other studies show that following forced over-expression in the medium of NTERA-2 cells, CREG inhibits cell cycle progression and induces cellular differentiation even in the absence of an inducer such as retinoic acid (1, 5).

Han et al. showed that CREG is significantly up-regulated at both the mRNA and protein levels during phenotypic conversion of proliferative and synthetic smooth muscle cells (SMCs) to non‑proliferative and differentiated SMCs in vitro (1). In addition, CREG over-expression in cultured SMCs may inhibit cellular proliferation and promote differentiation, whereas CREG knockdown prevents serum starvation-induced SMCs maturation and growth arrest (1). Moreover, CREG is down-regulated in the vascular media after balloon injury to the rabbit carotid artery (1). Adenovirus-mediated CREG over-expression in injured arteries inhibits SMCs proliferation and attenuates neointimal hyperplasia in vivo (1, 6). Research thus suggests that CREG plays a critical role in keeping cell or tissue in a mature, homeostatic state by antagonizing pathological de‑differentiation and overgrowth (1).

Of the several proteins that have been reported to interact with CREG, the cation-independent mannose-6-phosphate (M6P)/ insulin-like growth factor II receptor (IGF2R) has been shown to be required for its growth-suppressive activity (1, 6). Researchers' findings indicate that CREG protein may be a target for cell growth inhibition mediated by attenuation of IGF-II-induced endocytosis of its membrane receptor M6P/IGF2R (1). Delivering recombinant CREG protein in vivo may provide therapeutic benefits for some pathological proliferative diseases, such as arterial restenosis after angioplasty, atherosclerosis, and human cancers (1).