Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Feb 1;8(3):383-90.
doi: 10.4161/cc.8.3.7542. Epub 2009 Feb 3.

A New Link Between Epigenetic Progenitor Lesions in Cancer and the Dynamics of Signal Transduction

Affiliations
Free PMC article
Review

A New Link Between Epigenetic Progenitor Lesions in Cancer and the Dynamics of Signal Transduction

Winston Timp et al. Cell Cycle. .
Free PMC article

Abstract

Our recent study of the mechanism by which an epigenetic alteration, loss of imprinting (LOI) of Igf2, increases tumor risk, revealed a strong relationship between IGF2 dosage, the dynamics of signaling along the IGF2 axis, cell proliferation and tumor risk.(1) Colon epithelia in a mouse model with LOI of Igf2 showed increased sensitivity to IGF1R blockade and abrogation of premalignant lesion development in LOI(+) mice. These results are consistent with the epigenetic progenitor model of cancer,(2) in which epigenetic changes precede and heighten risk of cancer in response to oncogenic mutations. Thus, one can envision a highly targeted and focused chemoprevention strategy targeted to signaling pathways in nonmalignant cells that have undergone an epigenetic lesion, rather than a broad approach toward reversing epigenetic lesions that may have unintended consequences affecting the whole epigenome.

Figures

Figure 1.
Figure 1.
Schematic of Wnt/β-catenin pathway. (Left) In a naiïve cell, p-catenin, when produced, binds to the APC/Axin complex, and is phosphorylated first by CK1 a, then by GSK3p. This phosphorylation leads to inactivation. The Tcf factor in the nucleus is bound by Groucho, a member of the Grg transcription factor family, which inhibits transcription. β-catenin also has a role in cell-cell adhesion, forming a complex with actin, β-catenin and E-cadherin to form a desmosome. (Right) In contrast, when Wnt is present, it binds to the Frizzled/LRP6 receptor complex, activating Disheveled (Dsh), which acts to inactivate β-catenin degradation, either through sequestering Axin or through inactivation of GSK3β. The accumulation of β-catenin in the cell allows for accumulation in the nucleus, allowing β-catenin to bind to Tcf and activate transcription.
Figure 2.
Figure 2.
Normal imprinting of the Igf2/H19 locus. The imprinting control region (ICR) on the paternal chromosome is normally methylated, preventing the binding of the zinc-finger protein CTCF. This causes the upstream enhancer region (E) to act on the Igf2 gene, and silences H19. In contrast, the unmethylated ICR on the maternal chromosome allows CTCF binding, insulating the enhancer region from Igf2. This causes the expression of H19 and the silencing of Igf2.
Figure 3.
Figure 3.
Schematic of the IGF2 signaling pathway. IGF2 is present in the extracellular space, with free and IGFBP bound portions in equilibrium, acting to stabilize and control the concentration. IGF2 binds to IGF1R or INSR, which causes autophosphorylation of the receptor tyrosine kinase domain. The activated tyrosine kinase domain then acts to phosphorylate IRS, which then binds PI3K. PI3K acts to convert PIP2 to PIP3, which is balanced by the action of PTEN to convert PIP3 back to PIP2. PIP3 is a powerful second messenger, which, among other things, acts as a docking point for the pleckstrin homology domain of PKB/Akt. With Akt recruited to the membrane, it is then phosphorylated by PDK1 and PDK2, activating it. Akt then acts to phosphorylate a variety of factors, enhancing proliferation and preventing apoptosis. IGF1R may also activate other pathways, such as Shc/Grb2/SOS which activates the Ras pathway.
Figure 4.
Figure 4.
Model of IGF2 effects on colonic epithelia. (A) With normal, monoallelic expression of IGF2, the IGF1R receptor acts to stimulate growth and inhibits apoptosis (through CARD11) and differentiation (through GSK3p). This is coupled to the Wnt pathway, as they both inhibit GSK3p. (B) In the case of LOI of Igf2, the biallelic expression of Igf2 leads to more IGF1R expression, as well as a reinforcement of the growth pathway while inhibiting the differentiation and apoptotic pathways. (C) However, when an inhibitor of IGF1R action is applied, these pathways are curtailed, leading to an increase in apoptotic pathways and reestablishment of the differentiation equilibrium.

Similar articles

See all similar articles

Cited by 11 articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback