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The role of keratinocyte p53 in development of pigmented lesions

角质形成细胞 p53 在色素病变发展中的作用

基本信息

批准号：
9285695
负责人：
Neil Frederick Box
金额：
$ 7.78万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-20 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285695
关键词：
Acute Adolescence Apoptosis Ataxia BRAF gene Behavior Cell Cycle Arrest Cells Cellular Stress Chemicals Chemoprevention Childhood Chronic Cutaneous Melanoma DNA Damage DNA Repair Data Development Dose Doxycycline Elderly Environment Epidemiology Freckles Gene Expression Profiling Gene Targeting Genomics Growth Factor Guidelines Human Incidence Kinetics Lead Lesion Link Mediator of activation protein Melanocytic nevus Modeling Molecular Mus Mutate Mutation Neonatal Nevi and Melanomas Nevus Oncogene Activation Pathway interactions Pigments Play Predisposition Premalignant Protein p53 Protocols documentation Public Health Radiation exposure Radiation induced damage Risk Role Signal Transduction Site Skin Skin Cancer Skin tanning Stem Cell Factor Sunburn Sunlight TP53 gene Testing Tetanus Helper Peptide Transactivation Tumor Initiators UV Radiation Exposure Ultraviolet Rays Up-Regulation Western World cancer risk cancer type carcinogenesis foot genome integrity in vivo keratinocyte melanocyte melanoma migration mouse model novel novel strategies overexpression p53 Signaling Pathway paracrine photoprotection programs promoter protective effect public health relevance release factor senescence sensor transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Cutaneous malignant melanoma is the deadliest form of skin cancer. Ultraviolet radiation (UVR) in sunlight plays a causative role in melanoma development both as an initiator, through mutational activation of oncogenes such as BRAF, and as a promoter through effects on melanocyte migration and proliferation. While intense UVR resulting in sunburns is associated with melanoma risk, epidemiology shows that persistent lower level chronic exposure may protect against melanoma. This proposal focuses on the transcription factor p53, a sensor of genomic and cellular stress, and its action in keratinocytes after UVR. UVR activates p53 in keratinocytes, and depending on the level or type of damage, induces keratinocyte apoptosis (sunburn cells), and increases the expression of melanocyte growth factors, like KIT Ligand (KITLG), that control melanocyte proliferation and function; therefore p53 may well modulate melanoma risk. Indeed, in our Sooty Foot Ataxia (SFA) mice with constitutively high p53 levels in keratinocytes, we observed increased expression of keratinocyte-derived melanocyte growth factors and elevated melanocyte numbers. Importantly, these mice develop nevi and melanomas when subjected to a carcinogenesis protocol. These data strongly suggest a tumor promotional role for keratinocyte p53. Recently, we identified a key human cancer risk SNP in the p53 transactivation site at the KITLG locus that resulted in increased KITLG expression post-UVR. Together these data led us to hypothesize that strong p53 activation in keratinocytes stimulates a growth factor-rich environment that promotes the initiation and progression of pigmented lesions to melanoma; whereas persistent low p53 activation protects against melanoma development. This new role for p53 will be tested using both our constitutive keratinocyte p53 overexpressing SFA mice and our Doxycycline-inducible Tet-ON keratinocyte p53 overexpressing mice. In Aim 1, we will examine the impact of p53 activation in keratinocytes on the release of paracrine factors and on melanocyte proliferation. A detailed analysis of p53 pathway activity, including regulators and target genes, in the presence of different levels of p53 will allow us to construct a model of p53 action in keratinocytes that may explain the apparent link between acute intense UVR and melanoma risk and the association of chronic low UVR with protection from melanoma. In Aim 2, we will use our Tet-ON p53 mice in combination with the BrafV600E melanoma mouse model to study the paracrine effects of different levels of p53 activation in keratinocytes on nevus and melanoma development. We will investigate both acute intense p53 activation as a melanoma promoter, and low chronic p53 activation as a mediator of protection against UVR-induced melanoma. This proposal will yield a greater understanding of p53 signaling in keratinocytes and its impact on melanocytes and melanoma that may ultimately lead to new strategies for melanoma chemoprevention. The data generated in this proposal will be used to support an R01 application investigating these strategies.