Conditional deletion of insulin-like growth factor-I receptor in prostate epithelium | Academic Article individual record
abstract

Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that can influence growth, differentiation, and survival of cells expressing the cognate type 1 receptor (IGF-IR). To better understand cell autonomous IGF-IR signaling in the epithelial compartment of the prostate gland, we generated a conditional (Cre/loxP) prostate-specific IGF-IR knockout mouse model. In contrast to epidemiologic studies that established a correlation between elevated serum IGF-I and the risk of developing prostate cancer, we show that abrogation of IGF-IR expression in the dorsal and lateral prostate could activate extracellular signal-regulated kinase 1/2 signaling and cause cell autonomous proliferation and hyperplasia. Moreover, persistent loss of IGF-IR expression in dorsal and ventral lobes induced p53-regulated apoptosis and cellular senescence rescue programs, predicting that titration of IGF-IR signaling might facilitate growth of tumors with compromised p53 activity. Therefore, we crossed the mice carrying the prostate-specific IGF-IR knockout alleles into the transgenic adenocarcinoma of the mouse prostate model that is driven, in part, by T antigen-mediated functional inactivation of p53. Consistent with our prediction, prostate epithelial-specific deletion of IGF-IR accelerated the emergence of aggressive prostate cancer when p53 activity was compromised. Collectively, these data support a critical role for IGF-IR signaling in prostate tumorigenesis and identify an important IGF-IR-dependent growth control mechanism.

authors
author list (cited authors)
Sutherland, B. W., Knoblaugh, S. E., Kaplan-Lefko, P. J., Wang, F., Holzenberger, M., & Greenberg, N. M.
publication date
2008
published in
keywords
  • Cell AgingAdenocarcinomaAge FactorsAnimalsApoptosisCell ProliferationCellular SenescenceEpitheliumGene DeletionGene Expression Regulation, NeoplasticGene TargetingIntegrasesMaleMiceMice, Inbred C57BLMice, TransgenicOrgan SpecificityProstateProstatic HyperplasiaProstatic NeoplasmsReceptor, IGF Type 1