Down-regulation of cyclin G2 by insulin, IGF-I (insulin-like growth factor 1) and X10 (AspB10 insulin): role in mitogenesis

Abstract

The mechanisms whereby insulin analogues may cause enhanced mitogenicity through activation of either the IR (insulin receptor) or the IGF-IR (insulin-like growth factor 1 receptor) are incompletely understood. We demonstrate that in L6 myoblasts expressing only IGF-IRs as well as in the same cells overexpressing the IR, IGF-I (insulin-like growth factor 1), insulin and X10 (AspB10 insulin) down-regulate the mRNA expression level of the cell cycle inhibitor cyclin G2, as measured by qRT-PCR (quantitative reverse transcription-PCR), and induce cell growth measured by [6-(3)H]thymidine incorporation into DNA. Western blotting showed a marked down-regulation of cyclin G2 at the protein level in both cell lines. Overexpression of cyclin G2 in the two cell lines diminished the mitogenic effect of all three ligands. The use of specific inhibitors indicated that both the MAPK (mitogen-activated protein kinase) and the PI3K (phosphoinositide 3-kinase) pathways mediate the down-regulation of Ccng2. The down-regulation of CCNG2 by the three ligands was also observed in other cell lines: MCF-7, HMEC, Saos-2, R(-)/IR and INS-1. These results indicate that regulation of cyclin G2 is a key mechanism whereby insulin, insulin analogues and IGF-I stimulate cell proliferation.

Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

“…Insulin is a prominent growth factor, but its molecular targets regulating the cell cycle are still poorly defined . The Rb–E2F1 complex plays a pivotal role in cell cycle progression.…”

“…However, depending on the cell type, the PI3K–Akt and Ras–ERK1/2 signaling pathways are likely to be involved to variable degrees . While the molecular pathways mediating insulin‐induced metabolic actions are well characterized, the mechanisms whereby insulin stimulates mitogenesis and regulates the cell cycle and G 1 /S progression remain to be fully clarified . Insulin signaling and action are also tightly monitored by negative regulators, including the molecular adapter growth factor receptor binding protein 14 (Grb14) .…”

“…(10,11) While the molecular pathways mediating insulin-induced metabolic actions are well characterized, the mechanisms whereby insulin stimulates mitogenesis and regulates the cell cycle and G 1 /S progression remain to be fully clarified. (12,13) Insulin signaling and action are also tightly monitored by negative regulators, including the molecular adapter growth factor receptor binding protein 14 (Grb14). (9,14) We previously reported that Grb14, which is highly expressed in the liver, is an inhibitor of IR catalytic activity and that its downregulation improves IR signaling and hepatic glucose production in cultured hepatocytes.…”

GSK3 Protein Positively Regulates Type I Insulin-like Growth Factor Receptor through Forkhead Transcription Factors FOXO1/3/4

“…FOXO also activates the cell cycle inhibitor cyclin G 2 (24). Moreover, insulin and IGF-I have been reported to down-regulate the expression of cyclin G 2 as part of their mitogenic effect (25). Hence, FOXOs are considered as tumor suppressors.…”

Receptor Tyrosine Kinase Signal Transduction and the Molecular Basis of Signalling Specificity

“…Cyclin G2 was found to be markedly downregulated by insulin, insulin analogues and IGF-I in L6 myoblasts overexpressing the insulin receptor, as well as in several other cell types [ 98 , 99 ]. Overexpression of cyclin G2 inhibited cell proliferation induced by insulin, insulin analogues and IGF-I [ 99 ]. The use of specifi c inhibitors indicated that both the MAPK (mitogen-activated protein kinase) and the PI3K (phosphoinositide 3-kinase) pathways mediate the downregulation of cyclin G2.…”