ABSTRACT
In all vertebrates, insulin-like growth factors (IGF)-I and IGF-II, members of the insulin family proteins, play important roles in regulating growth, development, and metabolism (de Pablo et al., 1990, 1993; Stewart and Rotwein, 1996). Like all peptide hormones, IGFs are initially synthesized as prepropeptides containing an amino-terminal signal peptide, followed by the mature peptide of B, C, A, and D domains and a carboxyl terminal E-peptide domain. Through intracellular posttranslational processing, the signal peptide and the E-peptide are proteolytically cleaved off from the prepropeptide, and both the mature IGFs and E-peptides are secreted into the bloodstream (Rotein et al., 1986; Duguay, 1999). Molecular cloning and characterization of the IGF-I gene and its cDNA revealed the presence of multiple isoforms of IGF-I mRNA from sh to mammals. In human, three different species of IGF-I mRNAs encoding three isoforms of pro-IGF-I (i.e., pro-IGF-Ia, pro-IGF-Ib, and pro-IGF-Ic) were identied (Rotwein et al., 1986; Duguay, 1999) (Figure 19.1). These three isoforms of pro-IGF-I contain an identical mature IGF-I with 70 amino acid (aa) residues but different E-peptides of 30 aa (Ea), 77 aa (Eb), and 40 aa (Ec), respectively. The a-type E-domains are highly conserved among all vertebrates studied,
CONTENTS
19.1 Introduction ........................................................................................................................349 19.2 Anticancer Activities of rtEa4-and hEb-Peptide .......................................................... 351
19.2.1 Inhibition of Anchorage-Independent Cell Growth ......................................... 352 19.2.2 Inhibition of Invasion and Metastasis ................................................................ 356 19.2.3 Inhibition of Tumor-Induced Angiogenesis ...................................................... 356 19.2.4 Induction of Apoptosis .......................................................................................... 358
19.3 Regulation of Gene Expression by rtEa4-Peptide .........................................................364 19.3.1 Up-and Downexpression of Genes Regulated by rtEa4-Peptide ...................364 19.3.2 Effects of Signal Transduction Inhibitors on Gene Expression .......................366 19.3.3 Identication of the Receptor of rtEa4-Peptide..................................................366
