p53, possibly the single most important human tumor suppressor, has been found to be mutated in over half of all cancers. This study investigates the role insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) plays in mediating p53-induced apoptosis and cell cycle arrest. p53 has been shown to activate IGFBP-3 expression and apoptosis, and the p53-induced apoptosis can be reversed by treatment with IGF-1 and by IGFBP-3 blockade. IGFBP-3 is integrally involved in apoptosis as well as in growth inhibition, acting in both IGF-dependent and independent manners. The central hypothesis, that p53-induced apoptosis is mediated in part by the actions of IGFBP-3, underscores the experimental goals: to evaluate the physiologic significance of the p53/IGFBP-3 interaction and to elucidate its mechanisms of action. The mechanisms investigated will include the promoter sequences necessary for IGFBP-3 induction by genotoxic stress and hypoxia, the downstream effectors of IGFBP-3-mediated apoptosis and the IGFBP-3 domains required for inducing apoptosis. The possibility that IGFBP-3 is not the only IGFBP regulated by p53 will be explored. If successful, these studies may provide further understanding of the molecular events leading to apoptosis and delineate new means of cross-talk between the p53 and IGF axes. This is particularly important for diseases of dysregulated cell growth, given the recent findings of an association between elevated serum IGF-1 levels and increased risk of prostate, colorectal and lung cancer. Clarifying the role of IGFBP-3 mediated apoptosis as a protective factor may not only help to understand the significance of the IGF-1 association, but may also suggest novel approaches to the treatment and clinical management of cancer and other diseases involving dysregulated cell growth. These studies also reflect Dr. Grimberg?s long-term career goals of exploring the interrelatedness of endocrine and oncologic molecular biology principles and applying them to clinical problems of dysregulated growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK064352-04
Application #
6895209
Study Section
Subcommittee G - Education (NCI)
Program Officer
Hyde, James F
Project Start
2002-08-15
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$131,652
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Grimberg, Adda; Feemster, Kristen A; Pati, Susmita et al. (2011) Medically underserved girls receive less evaluation for short stature. Pediatrics 127:696-702
Grimberg, Adda; Ramos, Mark; Grundmeier, Robert et al. (2009) Sex-based prevalence of growth faltering in an urban pediatric population. J Pediatr 154:567-572.e2
Grimberg, Adda; Stewart, Elizabeth; Wajnrajch, Michael P (2008) Gender of pediatric recombinant human growth hormone recipients in the United States and globally. J Clin Endocrinol Metab 93:2050-6
Shi, Zonggao; Henwood, Maria J; Bannerman, Peter et al. (2007) Primary pigmented nodular adrenocortical disease reveals insulin-like growth factor binding protein-2 regulation by protein kinase A. Growth Horm IGF Res 17:113-21
Grimberg, Adda; Coleman, Carrie M; Shi, Zonggao et al. (2006) Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling. Cancer Biol Ther 5:1408-14
Sutter, Jennifer A; Grimberg, Adda (2006) Adrenocortical tumors and hyperplasias in childhood--etiology, genetics, clinical presentation and therapy. Pediatr Endocrinol Rev 4:32-9
Grimberg, Adda (2005) Cancer. Adv Exp Med Biol 567:305-39
Finnberg, Niklas; Kim, Seok-Hyun; Furth, Emma E et al. (2005) Non-invasive fluorescence imaging of cell death in fresh human colon epithelia treated with 5-Fluorouracil, CPT-11 and/or TRAIL. Cancer Biol Ther 4:937-42
Grimberg, Adda; Kutikov, Jessica Katz; Cucchiara, Andrew J (2005) Sex differences in patients referred for evaluation of poor growth. J Pediatr 146:212-6
Grimberg, Adda; Coleman, Carrie M; Burns, Timothy F et al. (2005) p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia. J Clin Endocrinol Metab 90:3568-74

Showing the most recent 10 out of 13 publications