Growth and Differentiation Signals by the Insulin-like Growth Factor 1 Receptor in Hemopoietic Cells Are Mediated through Different Pathways

Abstract

The type 1 insulin-like growth factor receptor (IGF-IR) plays an important role in the growth of cells both in vivo and in vitro. The IGF-IR is also capable of inducing differentiation in a number of cell types, raising the question of how the same receptor can send two seemingly contradictory signals, one for growth and one for differentiation. Using 32D cells, which are murine hemopoietic cells, we show that the activated IGF-IR can induce differentiation along the granulocytic pathway in a manner similar to the granulocyte colony-stimulating factor. We find that one of the major substrates of the IGF-IR, the insulin receptor substrate-1 inhibits IGF-I-mediated differentiation of 32D cells. In the absence of insulin receptor substrate-1, functional impairment of another major substrate of the IGF-IR, the Shc proteins, is associated with a decrease in the extent of differentiation. Although the end points of the respective pathways remain to be defined, these results show for the first time that IGF-I-mediated growth or differentiation of hemopoietic cells may depend on a balance between two of its substrates.

Efficient in vitro and in vivo gene regulation of a retrovirally delivered pro-apoptotic factor under the control of the Drosophila HSP70 promoter

“…Included in Figure 5 are the Western blots from the mixed population from which the clones were derived, and also from 32D-GR15-GR103 cells that have a non-inducible IRS-1. 25 There is a modest increase in expression at 39°C even with the noninducible promoter, but the difference between 32D-GR15-GR103 cells and the clones is dramatic. It seems therefore that this method gives with a single transduction, a population of cells in which all or most of the cells carry an inducible construct.…”

IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation

“…According to our hypothesis, a reduced level of IGF-IR compensates for the absence of IRS-1 expression, since high levels of IGF-IR, in the absence of IRS-1, lead to di erentiation (Valentinis et al, 1999b) …”

“…In fact, no IRS-1 mRNA is detectable in LNCaP cells (not shown). This was quite surprising, since IRS-1 is strongly mitogenic (Valentinis et al, 1999b; and can induce transformation of cells in cultures (D'Ambrosio et al, 1995;Tanaka et al, 1996). The IRS-1 gene is not deleted from these cells.…”

“…(1) ectopic expression of IRS-1 will increase cell adhesion and cell-to-cell aggregation; (2) IRS-1 expression ought to decrease cell motility; (3) wild type PTEN will decrease colony formation in soft agar, while PTEN plus IRS-1 will restore cloning e ciency in soft agar; (4) Over-expression of the IGF-IR in parental LNCaP cells (without IRS-1) will cause growth arrest, as predicted by Valentinis et al (1999b) and (5) A combination of IGF-IR and IRS-1 will restore anchorage independence and allow LNCaP cells to form tumors in nude mice. The aim of this paper is to test our hypothesis and to verify whether or not our predictions are correct.…”

“…This decrease would be obviated by a mutation in PTEN, which, through the disregulation of PI3-kinase, re-activates the Akt/PKB pathway. But a decrease in IGF-IR levels is also needed at this point, because high levels of IGF-IR in the absence of IRS-1, cause cell di erentiation (Valentinis et al, 1999b). This hypothesis makes several predictions for LNCaP cells:…”