Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes

Abstract

Insulin-like growth factor 2 (IGF2) and the transformation related protein 53 (Trp53) are potent regulators of cell growth and metabolism in development and cancer. In vitro evidence suggests several mechanistic pathway interactions. Here, we tested whether loss of function of p53 leads to IGF2 ligand pathway dependency in vivo. Developmental lethality occurred in p53 homozygote null mice that lacked the paternal expressed allele of imprinted Igf2. Further lethality due to post-natal lung haemorrhage occurred in female progeny with Igf2 paternal null allele only if derived from double heterozygote null fathers, and was associated with a specific gene expression signature. Conditional deletion of Igf2fl/fl attenuated the rapid tumour onset promoted by homozygous deletion of p53fl/fl. Accelerated carcinoma and sarcoma tumour formation in p53+/− females with bi-allelic Igf2 expression was associated with reductions in p53 loss of heterozygosity and apoptosis. Igf2 genetic dependency of the p53 null phenotype during development and tumour formation suggests that targeting the IGF2 pathway may be useful in the prevention and treatment of human tumours with a disrupted Trp53 pathway.

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

“…Alterations in the expression of genes in the H19-IGF2 imprint locus have been described in Beckwith-Wiedemann syndrome (BWS) [117] and Russell-Silver syndrome (RSS) [118], which are associated with risk for Wilms tumor, hepatoblastoma, and rhabdomyosarcoma. Bidirectional links between WT p53 and imprinted genes in the H19-IGF2 locus have been demonstrated in several studies [119–121]. Loss of imprinting of IGF2 accelerates tumor formation by inactivating WT p53 [119].…”

“…Bidirectional links between WT p53 and imprinted genes in the H19-IGF2 locus have been demonstrated in several studies [119–121]. Loss of imprinting of IGF2 accelerates tumor formation by inactivating WT p53 [119]. Maternally imprinted H19, which encodes a long noncoding RNA, has been shown to be negatively regulated by p53 [120].…”

Antitumor mechanisms when pRb and p53 are genetically inactivated

“… (a) briefly summarizes the reciprocal regulation between IGF2-IGF1R-PI3K(Pten)-Akt and p53 as discussed in the text. (b) displays the synthetic lethal relationship between IGF2 KO and p53 KO in embryogenesis and p53 deficient tumorigenesis reported by Haley et al ( 87 ). (c) summarizes the synthetic lethal relationship between specific PIP4K2A,B KO and p53KO ( 89 ).…”

“…IGF1R ligand IGF2 is often overexpressed in human cancers. Haley et al studied physiological relationship between IGF2 and p53 ( 87 ). Mating of IGF2 and Trp53 doubly heterozygous mice produced only 16 live births out of the expected 44 doubly deficient embryos, revealing partial synthetic lethality during embryogenesis.…”

Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth

“…Various animal models leading to IGF2 overexpression have demonstrated increased risk of malignancy, including mammary, lung, and colon cancers (6). However, these models often alter H19 expression, which may also play a role in tumorigenesis (19,20), or use transgenic overexpression of IGF2, resulting in levels not normally seen with aging (21,22).…”