The long-term objective of this proposal is to begin to understand the mechanism of UVB-induced skin cancer. Cancers of the skin are the predominant cancer diagnosed in the United States. In addition to the trauma skin cancer causes for its victims, the treatment of skin cancer is also a tremendous burden financially on our healthcare system. Although it is known that the principle carcinogen responsible for the generation of skin cancer is the UV component of sunlight, very little is known about the exact relationship between UV- exposure and the development of skin cancer. The activation of the insulin-like growth factor-1 receptor (IGF-1R) was shown to be a critical factor in determining how keratinocytes respond to UVB exposure. UVB exposure in the presence of activated IGF-1Rs permits keratinocytes to remain viable and not undergo apoptosis. However, a consequence of continued viability is that the irradiated keratinocytes lose the capacity to replicate. We define these two functions of the IGF- 1R in response to IJVB exposure as the induction of survival and senescence. In contrast, in the absence of IGF-1 binding, the same UVB exposure will result in the induction of apoptosis. A critical feature in this model is that in the absence of IGF-1R activation, keratinocytes that survive UVBitradiation still maintain the potential to proliferate. It is this proliferation, following UVB-induced DNA damage that may produce keratinocytes that have oncogenic potential In this proposal, we will begin to characterize the mechanism of how the IGF-1R protects normal human keratinocytes from UVB-induced apoptosis. This characterization will be accomplished through the creation of a model system, which will selectively and specifically inactivate the activity of the IGF-1 R. This model system will be used to identify key components of the IGF-1R mediated, UVB-response in human keratinocytes. Through the identification of these components of the UVB-response in human keratinocytes, therapeutic strategies for the prevention of LTVB-induced carcinogenesis can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011155-03
Application #
6611406
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Humble, Michael C
Project Start
2001-09-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$289,025
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Dermatology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Loesch, Mathew M; Collier, Ann E; Southern, David H et al. (2016) Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo. Mol Oncol 10:1245-54
Lewis, D A; Travers, J B; Somani, A-K et al. (2010) The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer. Oncogene 29:1475-85
Lewis, Davina A; Travers, Jeffrey B; Spandau, Dan F (2009) A new paradigm for the role of aging in the development of skin cancer. J Invest Dermatol 129:787-91
Lewis, Davina A; Yi, Qiaofang; Travers, Jeffrey B et al. (2008) UVB-induced senescence in human keratinocytes requires a functional insulin-like growth factor-1 receptor and p53. Mol Biol Cell 19:1346-53
Lewis, Davina A; Spandau, Dan F (2008) UVB-induced activation of NF-kappaB is regulated by the IGF-1R and dependent on p38 MAPK. J Invest Dermatol 128:1022-9
Lewis, Davina A; Spandau, Dan F (2007) UVB activation of NF-kappaB in normal human keratinocytes occurs via a unique mechanism. Arch Dermatol Res 299:93-101
Lewis, Davina A; Hengeltraub, Simone F; Gao, Feng C et al. (2006) Aberrant NF-kappaB activity in HaCaT cells alters their response to UVB signaling. J Invest Dermatol 126:1885-92
Mendonca, Marc S; Mayhugh, Brendan M; McDowell, Berry et al. (2005) A radiation-induced acute apoptosis involving TP53 and BAX precedes the delayed apoptosis and neoplastic transformation of CGL1 human hybrid cells. Radiat Res 163:614-22
Chuang, T-Y; Lewis, D A; Spandau, D F (2005) Decreased incidence of nonmelanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study. Br J Dermatol 153:552-7
Mahler, Bryon; Gocken, Todd; Brojan, Marija et al. (2004) Keratin 2e: a marker for murine nipple epidermis. Cells Tissues Organs 176:169-77

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