Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression?

Abstract

The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, IGF2BP3) belong to a conserved family of RNA-binding, oncofetal proteins. Several studies have shown that these proteins act in various important aspects of cell function, such as cell polarization, migration, morphology, metabolism, proliferation and differentiation. In this review, we discuss the IGF2BP family’s role in cancer biology and how this correlates with their proposed functions during embryogenesis. IGF2BPs are mainly expressed in the embryo, in contrast with comparatively lower or negotiable levels in adult tissues. IGF2BP1 and IGF2BP3 have been found to be re-expressed in several aggressive cancer types. Control of IGF2BPs’ expression is not well understood; however, let-7 microRNAs, β-catenin (CTNNB1) and MYC have been proposed to be involved in their regulation. In contrast to many other RNA-binding proteins, IGF2BPs are almost exclusively observed in the cytoplasm where they associate with target mRNAs in cytoplasmic ribonucleoprotein complexes (mRNPs). During development, IGF2BPs are required for proper nerve cell migration and morphological development, presumably involving the control of cytoskeletal remodeling and dynamics, respectively. Likewise, IGF2BPs modulate cell polarization, adhesion and migration in tumor-derived cells. Moreover, they are highly associated with cancer metastasis and the expression of oncogenic factors (KRAS, MYC and MDR1). However, a pro-metastatic role of IGF2BPs remains controversial due to the lack of ‘classical’ in vivo studies. Nonetheless, IGF2BPs could provide valuable targets in cancer treatment with many of their in vivo roles to be fully elucidated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-1186-z) contains supplementary material, which is available to authorized users.

IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts

“…6A). Because IGF2BP1 may affect RNAs stability after binding (13), BCL11A mRNA decay was examined after treatment with the transcription inhibitor actinomycin D. As shown in Fig. 6B, BCL11A transcripts decayed at the same rate in IGF2BP1-OE samples compared with control transductions, suggesting that IGF2BP1 is not affecting the stability of BCL11A mRNA.…”

“…IGF2BP1 and IGF2BP3 are expressed during early development and steadily decrease after birth in most tissues, but IGF2BP2 continues to be expressed in adult tissues (13,14). To confirm their expression Significance Fetal hemoglobin (HbF) expression is a tissue-and stage-specific marker of ontogeny in large mammals, which also has therapeutic importance for beta hemoglobinopathies.…”

“…Due to the large number of potential binding partners in erythroid cells, additional studies were performed upon both mRNA and protein expression levels of IGF2BP1-binding partners. Three previously reported (13,24,25) IGF2BP1-binding partners were initially studied: c-MYC, IGF2, and beta-actin. In the primary erythroblasts, no significant changes were observed at their mRNA or protein levels in the IGF2BP1-OE samples compared with empty vector control transductions (Fig.…”

“…We thus hypothesized that additional downstream elements of this RNA-binding regulatory cascade may be involved. Among the group of potential let-7 targets (12), IGF2BP1 and IGF2BP3 are generally silenced during mammalian development, whereas IGF2BP2 expression remains stable (12)(13)(14)(15). Here we provide a focused examination of IGF2BP1 in human erythroid tissues as well as its potential to affect hemoglobin profiles in cultured human adult erythroblasts.…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…This suite of proteins is unlikely to act on a single locus or a highly specific process because they provide tumor-forming competence to a diverse array of oncogenic mutations, including mutants in two different transcription factors (Prospero and Nerfin-1) and an RNA-binding protein (Brain tumor). All 3 proteins are conserved in mammals, 29,30,31 raising the question of whether they may have a similar function, and making it important to determine their mechanism of action in both Drosophila and mammals.…”