The most common malignancy occurring in humans is skin cancer, with an incidence that approaches that of all other cancer subtypes combined. Both human papillomavirus (HPV) and ultraviolet (UV) irradiation are risk factors for this disease. Immortalization by HPV may be an early stage in carcinogenesis, while UV may induce subsequent events both by inducing further mutations, as well as selecting for tumorigenic cells. HPV-16 E6/7-immortalized human keratinocytes were exquisitely sensitive to UVB-induced apoptosis compared to either vector-transduced or early passage (p7) E6/7 cells. DNA microarray analysis showed that, out of 16,000 genes monitored, three members of the Id protein family exhibit significant changes following UVB exposure; each Id was differentially regulated by UV in primary versus immortalized cells. Id proteins play important roles in differentiation, apoptosis, and tumorigenesis in a variety of other cell types.
The Specific Aims will therefore test the hypothesis that Id genes play a central role in modulating keratinocyte apoptosis and differentiation induced by acute UVB exposure both in cell culture and grafted human epidermis.
Specific Aim I will examine the genetic elements that are responsible for the differential regulation of Id2 and Id3 in primary and immortalized HFK.
Specific Aim II will delineate the roles of Id2 and Id3 in the regulation of apoptosis in human keratinocytes. The mechanism(s) of the gene- and cell-type specific response will be studied by investigating the factors that interact preferentially with Id2 and Id3.
Specific Aim III will generate a grafted human epidermis derived from keratinocytes that overexpress Id2 or Id3 to examine both the short-term (differentiation and apoptosis) and long-term (transformation) responses to UVB or topical carcinogens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA100443-01A1
Application #
6729489
Study Section
Radiation Study Section (RAD)
Program Officer
Okano, Paul
Project Start
2004-04-14
Project End
2009-03-31
Budget Start
2004-04-14
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$174,600
Indirect Cost
Name
Georgetown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Chen, You-Shin; Aubee, Joseph; DiVito, Kyle A et al. (2015) Id3 induces an Elk-1-caspase-8-dependent apoptotic pathway in squamous carcinoma cells. Cancer Med 4:914-24
DiVito, Kyle A; Simbulan-Rosenthal, Cynthia M; Chen, You-Shin et al. (2014) Id2, Id3 and Id4 overcome a Smad7-mediated block in tumorigenesis, generating TGF-?-independent melanoma. Carcinogenesis 35:951-8
DiVito, Kyle A; Trabosh, Valerie A; Chen, You-Shin et al. (2010) Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo. Pigment Cell Melanoma Res 23:795-808
Ray, Radharaman; Simbulan-Rosenthal, Cynthia M; Keyser, Brian M et al. (2010) Sulfur mustard induces apoptosis in lung epithelial cells via a caspase amplification loop. Toxicology 271:94-9
Trabosh, Valerie A; Divito, Kyle A; D Aguda, Baltazar et al. (2009) Sequestration of E12/E47 and suppression of p27KIP1 play a role in Id2-induced proliferation and tumorigenesis. Carcinogenesis 30:1252-9
Trabosh, Valerie Anne; Daher, Ahmad; Divito, Kyle A et al. (2009) UVB upregulates the bax promoter in immortalized human keratinocytes via ROS induction of Id3. Exp Dermatol 18:387-95
Ray, Radharaman; Keyser, Brian; Benton, Betty et al. (2008) Sulfur mustard induces apoptosis in cultured normal human airway epithelial cells: evidence of a dominant caspase-8-mediated pathway and differential cellular responses. Drug Chem Toxicol 31:137-48
Simbulan-Rosenthal, C M; Daher, A; Trabosh, V et al. (2006) Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes. Oncogene 25:3649-60
Simbulan-Rosenthal, Cynthia M; Ray, Radharaman; Benton, Betty et al. (2006) Calmodulin mediates sulfur mustard toxicity in human keratinocytes. Toxicology 227:21-35
Daher, Ahmad; Simbulan-Rosenthal, Cynthia M; Rosenthal, Dean S (2006) Apoptosis induced by ultraviolet B in HPV-immortalized human keratinocytes requires caspase-9 and is death receptor independent. Exp Dermatol 15:23-34

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