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Featured researches published by Renny Kavanagh.


Cancer Research | 2005

A-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes

Ana Luisa Kadekaro; Renny Kavanagh; Hiromi Kanto; Silva Terzieva; J. Hauser; Nobuhiko Kobayashi; Sandy Schwemberger; James Cornelius; George F. Babcock; Howard G. Shertzer; Glynis Scott; Zalfa A. Abdel-Malek

UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors alpha-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that alpha-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of alpha-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with alpha-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with alpha-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis.


Annals of the New York Academy of Sciences | 2003

Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival.

Ana Luisa Kadekaro; Hiromi Kanto; Renny Kavanagh; Zalfa A. Abdel-Malek

Abstract: The characterization of the melanocortin 1 receptor (MC1R) expressed on human melanocytes and the findings that certain mutations in the POMC gene or the MC1R gene result in red hair phenotype underscore the significance of melanocortins and MC1R in regulating human pigmentation. We demonstrated that human melanocytes respond to α‐melanocortin (α‐MSH) or ACTH with increased proliferation and melanogenesis, and to agouti signaling protein by abrogation of these effects. α‐MSH and ACTH were equipotent and more potent than β‐MSH, and γ‐MSH was the least potent in activating the MC1R and stimulating melanogenesis and proliferation of human melanocytes. We characterized the MC1R genotype in a panel of human melanocyte cultures and identified three cultures that were homozygous for Arg160Trp, heterozygous for Arg151Cys and Asp294His, and heterozygous for Arg160Trp and Asp294His substitutions, respectively. Those cultures failed to respond to α‐MSH with increase in cAMP levels, tyrosinase activity, or proliferation and had an exaggerated response to the cytotoxic effect of ultraviolet (UV) radiation. These loss‐of‐function mutations have been associated with red hair phenotype and increased risk for skin cancer. Melanocytes homozygous for Val29Met substitution in MC1R responded normally to α‐MSH and UVB, suggesting that this variant is a polymorphism. We observed that α‐MSH promotes human melanocyte survival by inhibiting the UV‐induced apoptosis independently of melanin synthesis. This effect was absent in human melanocytes with loss of function MC1R mutations. We predict that the survival effect of α‐MSH is caused by reduction of UV‐induced DNA damage and contributes to the prevention of melanoma.


The FASEB Journal | 2010

Melanocortin 1 receptor genotype: An important determinant of the damage response of melanocytes to ultraviolet radiation

Ana Luisa Kadekaro; Sancy A. Leachman; Renny Kavanagh; Viki B. Swope; Pamela B. Cassidy; Dorothy M. Supp; Maureen A. Sartor; Sandy Schwemberger; George F. Babcock; Kazumasa Wakamatsu; Shosuke Ito; Amy Koshoffer; Raymond E. Boissy; Prashiela Manga; Richard A. Sturm; Zalfa A. Abdel-Malek

The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α‐melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α‐melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation‐induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. non‐functional receptor to α‐melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α‐melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel‐Malek, Z. A. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J. 24, 3850–3860 (2010). www.fasebj.org


The FASEB Journal | 2006

Melanoma prevention strategy based on using tetrapeptide α-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity

Zalfa A. Abdel-Malek; Ana Luisa Kadekaro; Renny Kavanagh; Aleksandar Todorovic; Leonid Koikov; Joseph C. McNulty; Pilgrim J. Jackson; Glenn L. Millhauser; Sandy Schwemberger; George F. Babcock; Carrie Haskell-Luevano; James J. Knittel

Melanoma is the deadliest form of skin cancer, with no cure for advanced disease. We propose a strategy for melanoma prevention based on using analogs of α‐melanocyte stimulating hormone (α‐MSH) that function as melanocortin 1 receptor (MC1R) agonists. Treatment of human melanocytes with α‐MSH results in stimulation of eumelanin synthesis, reduction of apoptosis that is attributable to reduced hydrogen peroxide generation and enhanced repair of DNA photoproducts. These effects should contribute to genomic stability of human melanocytes, thus preventing their malignant transformation to melanoma. Based on these findings, we synthesized and tested the effects of 3 tetrapeptide α‐MSH analogs, Ac‐His‐D‐Phe‐Arg‐Trp‐NH2, n‐Pentadecanoyl‐ and 4‐Phenylbutyryl‐His‐D‐Phe‐Arg‐Trp‐NH2, on cultured human melanocytes. The latter two analogs were more potent than the former, or α‐MSH, in stimulating the activity of tyrosinase, thus melanogenesis, reducing apoptosis and release of hydrogen peroxide and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation (UVR). The above analogs are MC1R agonists, as their effects were abrogated by an analog of agouti signaling protein, the physiological MC1R antagonist, and were absent in melanocytes expressing loss‐of‐function MC1R. Analogs, such as 4‐Phenylbutyryl‐His‐D‐Phe‐Arg‐Trp‐NH2 with prolonged and reversible effects, can potentially be developed into topical agents to prevent skin photocarcinogenesis, particularly melanoma.—Abdel‐Malek, Z. A., Kadekaro, A. L., Kavanagh, R. J., Todorovic, A., Koikov, L. N., McNulty, J. C., Jackson, P. J., Millhauser, G. L., Schwemberger, S., Babcock, G., Haskell‐Luevano, C., Knittel, J. J. Melanoma prevention strategy based on using tetrapeptide α‐MSH analogs that protect human melanocytes from UV‐induced DNA damage and cytotoxicity. FASEB J. 20, E888–E896 (2006)


Journal of Cell Science | 2002

Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation

M. Cathy Scott; Kazumasa Wakamatsu; Shosuke Ito; Ana Luisa Kadekaro; Nobuhiko Kobayashi; Joanna Groden; Renny Kavanagh; Takako Takakuwa; Victoria Virador; Vincent J. Hearing; Zalfa A. Abdel-Malek


Pigment Cell Research | 2003

Cutaneous Photobiology. The Melanocyte vs. the Sun: Who Will Win the Final Round?

Ana Luisa Kadekaro; Renny Kavanagh; Kazumasa Wakamatsu; Shosuke Ito; Michelle Pipitone; Zalfa A. Abdel-Malek


Pigment Cell Research | 2006

Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes.

J. Hauser; Ana Luisa Kadekaro; Renny Kavanagh; Kazumasa Wakamatsu; Silva Terzieva; Sandy Schwemberger; George F. Babcock; M. B. Rao; Shosuke Ito; Zalfa A. Abdel-Malek


Pigment Cell Research | 2006

Diversity of pigmentation in cultured human melanocytes is due to differences in the type as well as quantity of melanin.

Kazumasa Wakamatsu; Renny Kavanagh; Ana Luisa Kadekaro; Silva Terzieva; Richard A. Sturm; Sancy A. Leachman; Zalfa A. Abdel-Malek; Shosuke Ito


Journal of Investigative Dermatology | 2002

Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes

Akihiro Tada; Elizabeth Pereira; Dana Beitner-Johnson; Renny Kavanagh; Zalfa A. Abdel-Malek


Journal of Medicinal Chemistry | 2005

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH2 Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

Aleksandar Todorovic; Jerry Ryan Holder; Rayna M. Bauzo; Joseph W. Scott; Renny Kavanagh; Zalfa A. Abdel-Malek; Carrie Haskell-Luevano

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Silva Terzieva

University of Cincinnati

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J. Hauser

University of Cincinnati Academic Health Center

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George F. Babcock

Shriners Hospitals for Children

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Sandy Schwemberger

Shriners Hospitals for Children

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