Nuclear actions of insulin-like growth factor binding protein-3

Abstract

In addition to its actions outside the cell, cellular uptake and nuclear import of insulin-like growth factor binding protein-3 (IGFBP-3) has been recognized for almost two decades, but knowledge of its nuclear actions has been slow to emerge. IGFBP-3 has a functional nuclear localization signal and interacts with the nuclear transport protein importin-β. Within the nucleus IGFBP-3 appears to have a role in transcriptional regulation. It can bind to the nuclear receptor, retinoid X receptor-α and several of its dimerization partners, including retinoic acid receptor, vitamin D receptor (VDR), and peroxisome proliferator-activated receptor-γ (PPARγ). These interactions modulate the functions of these receptors, for example inhibiting VDR-dependent transcription in osteoblasts and PPARγ-dependent transcription in adipocytes. Nuclear IGFBP-3 can be detected by immunohistochemistry in cancer and other tissues, and its presence in the nucleus has been shown in many cell culture studies to be necessary for its pro-apoptotic effect, which may also involve interaction with the nuclear receptor Nur77, and export from the nucleus. IGFBP-3 is p53-inducible and in response to DNA damage, forms a complex with the epidermal growth factor receptor (EGFR), translocating to the nucleus to interact with DNA-dependent protein kinase. Inhibition of EGFR kinase activity or downregulation of IGFBP-3 can inhibit DNA double strand-break repair by nonhomologous endjoining. IGFBP-3 thus has the ability to influence many cell functions through its interactions with intranuclear pathways, but the importance of these interactions in vivo, and their potential to be targeted for therapeutic benefit, require further investigation.

Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer

“…IGFBP-3 may potentiate gastric cancer cell division and invasion that contradicts previous findings of its role as a tumor suppressor [26]. There may be multiple factors that can influence IGFBP-3 expression, and its expression may have both positive and negative effects on tumor development as reported previously [24, 25, 41]. …”

“…IGFBP-3 inhibits cell growth and apoptosis in some circumstances but stimulates cell growth and survival in others [24–26]. IGFBP-3 is known to bind nuclear receptors of retinoic acid, vitamin D, peroxisome proliferator-activated receptor γ, nuclear hormone receptor 77, and epidermal growth factor receptors as well as the protein kinase catalytic subunits of DNA repair enzymes [25]. IGFBP-3 is known as a transcriptional target of the tumor suppressor protein p53, which modulates IGFBP-3 [26, 27].…”

40 YEARS OF IGF1: IGF-binding proteins

“…It entered the nucleus via interaction of a C-terminal bipartite nuclear 364 localisation sequence with importin-β (Baxter 2015;Schedlich, et al 2000). Within the nucleus, 365 IGFBP-3 interacted with receptors including RXR-α, PPAR-γ, the vitamin D receptor and Nur77, 366 leading to some of its effects on apoptosis, proliferation and differentiation.…”

“…Within the nucleus, 365 IGFBP-3 interacted with receptors including RXR-α, PPAR-γ, the vitamin D receptor and Nur77, 366 leading to some of its effects on apoptosis, proliferation and differentiation. Nuclear IGFBP-3 also 367 had a role in DNA damage repair (Baxter 2015;Lin, et al 2014;Liu, et al 2000), and it activated 368 autophagy in bronchial epithelial cells by a mechanism involving translocation of the transcription 369 factor Nur77 from the nucleus (Yin, et al 2017). Further studies are required to enhance our 370 incomplete understanding of the cellular uptake and nuclear actions of IGFBP-3.…”

Osteogenic Sarcoma: A 21st Century Review

“…Nevertheless, the plasma membrane is suspected to be a significant barrier in the transportation from the extracellular compartment. A nuclear retinoid X receptor α has been shown to be necessary for IGFBP3 induced apoptosis, and RXR ligands were additive with IGFBP3 in inducing apoptosis (65).…”