Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Transformation potential of human insulin receptor.
Diss Abstr Int [B]; 54(8):3990 1994. Unique Identifier : AIDSLINE ICDB/95606433 Du DY; Rockefeller Univ.
Abstract:
The transforming potential of human insulin receptor (hIR) previously has been demonstrated by transfecting chicken embryo fibroblasts (CEFs) with 5'-truncated hIR cDNAs, which had been fused in frame to RSV gag sequences (gag-IR fusion). The investigation of the molecular basis for hIR transformation activation is the focus of this thesis. A number of 5' and 3' deletion mutants of hIR cDNAs were constructed into retroviral vectors and their transforming and tumorigenic properties were examined subsequently. The results from 5' deletion mutant studies indicate that (1) 5' truncation of hIR cDNAs is not sufficient to result in transformation of CEFs; (2) fusion of 3' hIR to retroviral gag or env sequences is required to activate its transforming potential; and, (3) sites on hIR involved with autophosphorylation appear to be important for transformation of CEF. In addition, an env-IR fusion mutant is capable of inducing fibrosarcomas in chickens. Comparative studies with the N-terminal deletion and fusion mutants indicate that increased tyrosine protein kinase (TPK) activity of the IR proteins correlates with greater transforming potential. However, the tumorigenicity and transforming potential of these mutants were less than that of gag-IR, a spontaneously-arising mutant containing a larger N-terminal deletion in the hIR fusion sequences. Further studies indicate that deletion of 12 to 25 amino acids from the gag-hIR C-terminus increased transformation activity slightly; in contrast, deletion of 66 to 70 amino acids from the C-terminus markedly increased transformation of CEF but failed to induce tumors in chickens. None of the C-terminal deletion mutants showed substantial alteration in their TPK activity in vitro (cell extracts) and in vivo (living cells). Transformation activities were shown to correlate with metabolic activities (glucose uptake, lipid synthesis and amino acid uptake) in CEFs transfected with various C-terminal deletion mutants. Thus, hIR C-terminus seems to act as a negative effector on the transforming potential of the gag-IR protein. Thus, the human insulin receptor seems to have multiple N- or C-terminal domains which regulates its transforming potential. The possible biochemical events of hIR oncogenic activation include an elevated TPK activity and an abnormal interaction of mutant receptors with signal-transducing proteins. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-02379)
Keywords: Animal Cell Transformation, Neoplastic/*GENETICS/*METABOLISM Gene Deletion Gene Products, gag/GENETICS Mutation Protein-Tyrosine Kinase/METABOLISM Receptors, Insulin/*GENETICS/*METABOLISM THESIS 950430
M9541143
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
