IGF2: Epigenetic regulation and role in development and disease

Abstract

Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted – only one allele is active, depending on parental origin – and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.

Introduction

In the early 1900s, the innovative surgeon Alexis Carrel experimented with maintaining tissues and whole organs in vitro, hoping to advance techniques in organ transplantation. Carrel observed that certain tissue extracts could induce cell proliferation, and he published his findings with this disclaimer:

“Possibly the finding of the activating power of tissue extracts will have no immediate practical application. Nevertheless, it may be indirectly useful by leading to the discovery of some of the factors determining the growth of tissues and of the unknown laws of cell dynamics … [1].”

Carrel was mistaken that this finding would have no practical application—rather, it pioneered the discipline of tissue culture and the widespread use of serum to support in vitro cell growth. He was right, however, that this “activating power” would eventually lead to the discovery of growth factors, many of which were isolated and characterized in the decades that followed. Two of these factors, which were structurally similar to insulin, had many effects on cell growth and differentiation. In 1987, after 30 years of confusing nomenclature, these proteins were designated as insulin-like growth factor I (IGF1) and insulin-like growth factor II (IGF2) (Table 1).

The IGFs regulate cell growth and differentiation in many species. The anabolic functions of growth hormone are largely mediated by IGF1, which designates IGF1 as a major determinant of somatic growth [10]. Rare mutations in the human IGF1 gene lead to severe growth inhibition and mental retardation [11]. Igf1-null mice are born at 60% of normal birth weight, and the few that survive to adulthood are less than one-third the size of normal mice [12], [13]. On the other hand, IGF2 is virtually dispensable for post-natal development in mice, since Igf2 expression is almost entirely limited to the embryo in rodents [14]. At birth, Igf2-null mice are also growth-impaired but are otherwise normal, and subsequent growth proceeds at normal rates [13].

These studies support a somewhat redundant role for IGF2; furthermore, its designation as the “second” IGF seems to have relegated it to a lesser role than IGF1. However, IGF2 is the predominant IGF in adult humans (reviewed in Ref. [15]), and inappropriate IGF2 expression is implicated in a growing number of diseases (reviewed in Ref. [16]). The importance of IGF2 is highlighted by its complex and multifaceted regulation. The gene that codes for IGF2 is imprinted such that only one allele is expressed, depending on parental origin [14]. Besides the intriguing mechanisms that surround its imprinted expression, IGF2 is further modulated by a concert of differentially expressed proteins and receptors that determine IGF availability (reviewed in Ref. [17]). This review will examine the complex epigenetic regulation of the IGF2 gene and provide a broad introduction to IGF2 signaling. The ability of IGF2 to stimulate cell proliferation and differentiation will be reviewed, which will lead to a discussion on its involvement in various cancers and other diseases. The angiogenic functions of IGF2 will be addressed, and conclude with a proposal that IGF2 is a key mediator facilitating the angiogenic activity of sonic hedgehog (Shh).