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Mechanism of ultraviolet light-induced signaling transduction in skin photoaging and cancer (Molecular mechanisms by which ultraviolet (UV) irradiation from the sun damages human skin)

Gary Fisher, PhD and Yiru Xu, PhD

Epidermal growth factor receptor (EGFR) activation has been demonstrated as crucial for a wide range of UV irradiation-induced responses. Investigations to understand the molecular mechanisms by which UV irradiation activates EGFR resulted in the novel discovery that EGFR is maintained in an inactive state by protein tyrosine phosphatase kappa (RPTP-κ). UV irradiation inhibits RPTP-κ, thereby allowing EGFR to become activated. This new understanding of EGFR regulation by RPTP-κ has profound impact for: (1) fundamental knowledge regarding growth factor receptor regulation, (2) design of new therapeutic approaches to impede sun-induced skin aging, and (3) cancer biology, since misregulation of EGFR is a common driving force for many epithelial cancers.

Receptor Protein Tyrosine Phosphatase-kappa Regulation of EGFR

Premature skin aging occurs in all persons to varying degrees as a result of normal day-to-day outdoor activities. It is especially severe in persons with high levels of sun exposure due to occupation or lifestyle. Our research in this area seeks to understand the mechanisms by which ultraviolet (UV) irradiation from the sun damages human skin and causes premature skin aging and skin cancer.

Epidemiological studies worldwide have revealed a direct connection between the incidence of skin cancer and exposure to UV irradiation. Skin cancer is the most common type of cancer in the Caucasian population of the United States; with more than 500,000 to 1,000,000 cases diagnosed each year. The annual cost of treatment in the U.S. is estimated to be between $500 million and $1 billion. These findings are directly relevant to public health care in the largest sense, yet knowledge regarding the mechanisms by which solar UV irradiation damages skin is far from complete.

Ultraviolet irradiation damages human skin by at least two interdependent, but distinct, mechanisms:

DNA damage, resulting in genetic mutations that lead to cellular transformation; and activation of signal transduction pathways, that strongly induce matrix metalloproteinases and other gene products which promote a local tissue environment conductive to cancer formation. Emerging evidence indicates that tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) is a primary driving force by which UV irradiation stimulates signal transduction pathways that induce matrix metalloproteinases.

Our current research is elucidating the molecular mechanisms by which UV irradiation increases EGFR tyrosine phosphorylation and is testing the hypothesis that receptor-type protein tyrosine phosphatase-κ (RPTP-κ) specifically dephosphorylates EGFR. Reversible inhibition of RPTP-κ by UV-generated oxidative stress results in increased EGFR tyrosine phosphorylation, which drives downstream signal transduction pathways. Our specific aims are to:

  1. Determine regulation of EGFR tyrosine phosphorylation and signaling by RPTP-κ,
  2. Determine substrate specificity of RPTP-κ,
  3. Determine functional domains of RPTP-κ, and
  4. Determine the role of co-localization of EGFR and RPTP-κ in caveolin-enriched membrane rafts in regulation of EGFR tyrosine phosphorylation and signaling.

This new understanding of EGFR regulation by RPTP-κ has profound impact for: (1) fundamental knowledge regarding growth factor receptor regulation, (2) design of new therapeutic approaches to impede sun-induced skin aging, and (3) cancer biology, since misregulation of EGFR is a common driving force for many epithelial cancers.

Grant Number: 1R01ES012920-01A2
ICD: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
IRG: ACTS

References

  1. Fisher GJ, Datta S, Wang ZQ, Li XY, Quan T, Chung, JH, Kang S, Voorhees JJ. c-Jun dependent inhibition of cutaneous procollagen transcription following ultraviolet irradiation is reversed by all-trans retinoid acid. J Clin Invest. 2000;106(5):663-670.
  2. Kang S, Chung JH, Lee JH, Fisher GJ, Wan YS, Duell EA, Voorhees JJ. Topical N-acetyl cysteine and genistein prevent ultraviolet light-induced signaling that leads to photoaging in human skin in vivo. J Invest Dermatol. 2003;120:835-841.
  3. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y Datta S, Voorhees JJ. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138(11):1462-1470.

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