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The insulin-like growth factor-II (IGF-II) receptor (IGF2R) regulates the level or activity of numerous proteins, including factors that control growth and differentiation. Frequent loss or inactivation of this receptor in a diverse group of tumors indicates that it may act as a tumor suppressor, but it is not known which functions of this receptor are selected against in the tumors. Lysosomal targeting and degradation of the growth-promoting IGF-II has been proposed as a mechanism for the tumor suppressor effects of IGF2R. As a genetic test of this hypothesis in vivo, we have produced Igf2r transgenic mice that ubiquitously express the transgene and have crossed these mice with mice that develop mammary tumors as a consequence of Ig f2 overexpression. Our findings indicate that the presence of the Igf2r transgene delays mammary tumor onset and decreases tumor multiplicity in Igf 2 transgenic mice. These findings are relevant to human tumors and preneoplastic conditions accompanied by altered IGF2 expression.

The insulin-like growth factor II (IGFII) is a mitogen for a number of cell types in vitro and is required for normal embryonic growth. It has been hypothesized that overexpression of IGF2 is responsible for the increased growth and tumor predisposition in patients with Beckwith-Wiedemann syndrome. Association of increased levels of IGFII with increased growth is also incorporated in a current model for the evolution of Igf2 imprinting. Different experimental approaches to increasing IGFII levels in the mouse have yielded different results with respect to its effects on growth, viability, and tumor development. To investigate the consequences of IGf2 overexpression in the embryonic period, without alterations in the activity of other genes, we produced transgenic mice that express the Igf2 gene under the control of the H19 enhancers. Transgene expression in the embryonic period had no significant effect on the overall size of the embryos, but was associated with perinatal lethality in homozygous, and some heterozygous, mice. A large fraction of homozygous mice also developed a cleft palate. These findings indicate that overexpression of Igf2 can have an adverse effect on viability in the absence of a pronounced effect on overall body growth. The results are consistent with the view that growth and perinatal viability are affected differently by Igf2 overexpression in endodermal and mesodermal tissues.

The murine Ick gene is closely related to a family of cellular protooncogenes and encodes a lymphocytespecific, membrane-associated protein tyrosine kinase. We and others have demonstrated that the Ick gene is rearranged and overexpressed in the murine lymphoma LSTRA, most likely as a result of the insertion of Moloney murine leukemia virus DNA immediately adjacent to the gene. We now report that the Ick gene is located at the distal end of murine chromosome 4 and on human chromosome 1 at position lp32-35 near a site of frequent structural abnormalities in human lymphomas and neuroblastomas. These results raise the possibility that structural alteration of the ick gene through chromosomal rearrangement may contribute to transformation in human malignant disease.At least twelve genes encoding protein tyrosine kinases have been implicated in neoplastic transformation in mammalian cells (1, 2). Broadly speaking, characterized protein tyrosine kinase genes can be divided into two subfamilies. The first -encodes a group of cell-surface receptors that mediate mitogenesis. Ligands for these receptors are in three cases known, the epidermal growth factor (EGF) receptor (3), the insulin receptor (4), and the colony-stimulating factor 1 (CSF-1) receptor (5), while two other members of this subfamily encode receptor structures for which ligands are at present unidentified, neu (6, 7) and trk (8). A second subfamily of protein tyrosine kinase genes encodes a group of proteins that are typically membrane-associated but which lack recognizable transmembrane domains, for example abl, fgr, src, and lck** (1, 2, 9, 10). The protein tyrosine kinase oncogenes were originally identified as components of acutely transforming retroviruses or through transformation of cultured fibroblasts via transfection of tumor DNA (1, 2). In at least one case, the t(9;22) translocation of human chronic myelogenous leukemia, activation of a protein tyrosine kinase protooncogene (abi) results from a spontaneous chromosomal rearrangement (11,12). Thus protein tyrosine kinases may in some cases be involved in the specific chromosomal abnormalities frequently detected in human and murine neoplasia.The murine Ick gene encodes a lymphocyte-specific, membrane-associated protein tyrosine kinase of unknown function. We and others have demonstrated that this gene is rearranged and overexpressed in the murine lymphoma LSTRA, most likely as a result of insertion of Moloney murine leukemia virus sequences immediately upstream of the gene (9, 10). We now report that the Ick gene is located on human chromosome 1 at position 1p32-35 in a site of frequent structural abnormalities in human lymphomas and neuroblastomas. These results suggest that structural alteration of the lck gene through chromosomal rearrangement may occasionally contribute to transformation in human malignant disease. (14). Hybridization of the lck probe to mitotic chromosomes was performed by a modification of the method of Harper and Saunders (15). Briefly, chromosome slide preparatio...