Table 2 Mechanisms of increased IGF-2 gene/protein activities

Loss or imprinting (LOI)

Maternal allele becomes re-imprinted; transcription occurs from two IGF-2 alleles (23–26,77–91).

Loss of heterozygosity (LOH)

LOH is associated with duplication of the active paternal IGF-2 allele; transcription occurs from two IGF-2 alleles leading to higher mRNA level (93–98).

Altered binding proteins

Cleavage of IGF BPs by binding protein-specific proteases increase IGF-2 activity (69,100–102).

Loss of transcriptional suppressor protein

Suppressor proteins (WT-1, p53, and possibly CTCF), which bind to sequences in the IGF-2 enhancer/promoter regions, prevent transcription of IGF-2; when absent or mutated IGF-2 gene transcription increases (104–108).

Activation of transcription factors

Those that positively regulate IGF-2 (104–108).

Altered IGF-2 receptor/mannose-6-phosphate

Mutation in IGF-2 binding site required for the degradation of the IGF-2 decreases IGF-2 bioavailability (57–64).