Mechanisms of Cytokine-Induced IGF -I Insensitivity in Cancer Cells
Shen, Wen-Hong
This item is only available for download by members of the University of Illinois community. Students, faculty, and staff at the U of I may log in with your NetID and password to view the item. If you are trying to access an Illinois-restricted dissertation or thesis, you can request a copy through your library's Inter-Library Loan office or purchase a copy directly from ProQuest.
Permalink
https://hdl.handle.net/2142/83567
Description
Title
Mechanisms of Cytokine-Induced IGF -I Insensitivity in Cancer Cells
Author(s)
Shen, Wen-Hong
Issue Date
2003
Doctoral Committee Chair(s)
Kelley, Keith W.
Department of Study
Animal Sciences
Discipline
Animal Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Oncology
Language
eng
Abstract
Cell growth is a balance between proliferation and cell death, and cellular signaling pathways in response to both extracellular and intracellular stimuli control it. The data presented in this dissertation are aimed at understanding regulatory links between the endocrine and immune systems, focusing on how proinflammatory cytokines impair hormone actions on cellular growth. The prototypical proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), inhibit IGF-I-promoted DNA synthesis in human MCF-7 breast adenocarcinoma cells, T-47D breast ductal carcinoma cells, murine FDCP progenitor myeloid cells and human promyeloid HL-60 cells. Flow cytometry confirmed that all three cytokines suppress IGF-I-induced DNA synthesis by preventing cells from entering the S phase of the cell cycle, leading to G1 arrest in MCF-7 cells. TNFalpha and IL-1beta act by inhibiting the ability of IGF-I to tyrosine phosphorylate insulin receptor substrate-1 (IRS-1), to induce accumulation of both E2F-1 and cyclin A, to hyperphosphorylate retinoblastoma (RB), and to induce enzymatic activity and association of Cdk2 with cyclin A. The cytostatic property of these cytokines was also shown by their ability to block IGF-I-stimulated luciferase activity of a cyclin A promoter reporter. Deletion of an E2F recognition site from this reporter eliminates the regulatory effects of both IGF-I and TNFalpha/IL-1beta on cyclin A transcription, indicating an essential role for E2F-1 in mediating this cross talk. Moreover, knockdown experiments using E2F-1 siRNA abrogate IGF-I-induced cyclin A accumulation and RB hyperphosphorylation. These finding demonstrates that IGF-I stimulation of E2F-1 synthesis triggers G1-S progression by inducing cyclin A and inactivating RB. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, but not the mammalian target of rapamycin (mTOR) or mitogen-activated protein kinase (MAPK) pathways, is required for IGF-I to hyperphosphorylate RB and to induce both E2F-1 and cyclin A accumulation. Prolonged Akt phosphorylation serves as a convergent target for cytokines to antagonize IGF-I promoted G1-S progression. Collectively, experiments in this dissertation have identified critical growth-promoting proteins that are targeted by both IGF-I and proinflammatory cytokines, which offers a new model by which cytokines suppress cell growth by impairing signals from the IGF receptor, leading to IGF-I insensitivity.
Use this login method if you
don't
have an
@illinois.edu
email address.
(Oops, I do have one)
IDEALS migrated to a new platform on June 23, 2022. If you created
your account prior to this date, you will have to reset your password
using the forgot-password link below.
