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Tsing Cheng, Ph.D.

Tsing Cheng, Ph.D. Dysregulation of p53 in melanoma mediated by loss of OCA2 Outrun the Sun Melanoma Research and Education Forum Indianapolis, October 18, 2012. Melanocyte and melanoma. Melanocyte: Specialized cell that produces melanin (pigment)

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Tsing Cheng, Ph.D.

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  1. Tsing Cheng, Ph.D. Dysregulation of p53 in melanoma mediated by loss of OCA2 Outrun the Sun Melanoma Research and Education Forum Indianapolis, October 18, 2012

  2. Melanocyte and melanoma Melanocyte: • Specialized cell that produces melanin (pigment) • Specific proteins for the production of melanin including tyrosinase & OCA2 (Oculocutaneous Albinism type 2) Melanoma: • Skin cancer originating from melanocytes • High resistance to chemotherapy (chemoresistance): • Melanocytes can adapt to the harsh environment of the skin • New treatment options are necessary Understanding the biological mechanisms that underlie melanoma initiation, progression, and chemoresistance provides targets for future therapies Dysregulation of p53 in melanoma mediated by loss of OCA2

  3. OCA2 and melanoma Role of OCA2in melanocyte transformation and melanoma resistance? • OCA2 gene is frequently downregulated in melanoma • OCA2 polymorphisms are associated with increased risk of melanoma • Increased resistance to chemotoxins • Differential expression of p53 pathway in OCA2-null mouse melanocytes Is loss of OCA2 involved in dysregulation of p53 function in melanoma? Dysregulation of p53 in melanoma mediated by loss of OCA2

  4. p53: sensor of cell stress • Normal conditions: degradation and inactivation of p53 by MDM2 & MDM4 • Cellular stress: activation of p53 p53 plays multiple roles in: • cell cycle arrest • programmed cell death (apoptosis) Cell death Recovery p53 plays a crucial role in tumor suppression Dysregulation of p53 in melanoma mediated by loss of OCA2

  5. p53 and cancer Dysfunction of p53: survival of damaged cells → cancer Mutations in p53 gene (TP53) are common in most human cancers: • Lung cancer: 50-80% • Colorectal cancer: 40-60% • Non-melanoma skin cancer (BCC & SCC): 50-60% However, p53 gene is intact in ~90% of melanomas! Still, cancers can find other ways to dysregulate p53, and recent studies provide evidence that suggests a role for p53 in melanomagenesis Dysregulation of p53 in melanoma mediated by loss of OCA2

  6. MDM4 overexpression in melanoma • MDM4 protein expression was significantly increased in 69% of melanomas compared to normal melanocytes • High MDM4 levels inhibit apoptosis in melanoma by antagonizing p53 Gembarska et al., 2012 Dysregulation of p53 in melanoma mediated by loss of OCA2

  7. Differential gene expression of p53 pathway in Oca2-null mouse melanocytes activators inhibitors Oca2-null vs. wildtype; fold change > 2 Dysregulation of p53 in melanoma mediated by loss of OCA2

  8. Ultraviolet irradiation does not activate p53 in Oca2-null mouse melanocytes normal Oca2-null - - + + • UV irradiation causes DNA damage • Activation of p53 in response to UV irradiation in normal melanocytes, but not in Oca2-null cells UV: p53 Ser 6 Ser 15 Ser 20 Ser 46 Dysregulation of p53 in melanoma mediated by loss of OCA2

  9. Increased chemoresistance in Oca2-null mouse melanocytes Mouse melanocytes that do not express Oca2 are more resistant to the chemotoxin ATO Staleva et al., 2002 Dysregulation of p53 in melanoma mediated by loss of OCA2

  10. Inhibition of MDM2 increases chemosensitivity • Use of specific inhibitor of MDM2 • ATO has no effect on Oca2-null mouse melanocyte viability • Combined treatment of ATO with MDM2-inhibitor decreased cell viability greatly Dysregulation of p53 in melanoma mediated by loss of OCA2

  11. Reintroducing OCA2 decreases chemoresistance YUSAC2: OCA2-negative human melanoma cell line Dysregulation of p53 in melanoma mediated by loss of OCA2

  12. Summary • p53 plays an important role in tumor suppression • p53 pathway is involved in melanoma despite a low p53 mutation frequency • Dysregulation of p53 function in melanoma could be mediated via other mechanisms such as overexpression of p53 inhibitors • Loss of OCA2 could mediate dysregulation of p53 pathway in melanoma • Indications that loss of OCA2 expression is involved in melanocyte transformation and melanoma chemoresistance Dysregulation of p53 in melanoma mediated by loss of OCA2

  13. Future directions • Is there a correlation between loss of OCA2 and p53 dysregulation in melanoma? • Reintroduction of OCA2: • Increase melanoma chemosensitivity • Restoration of p53 pathway? • Can we increase melanoma chemosensitivity by modulating the p53 pathway? • MDM2- & MDM4-inhibitors Dysregulation of p53 in melanoma mediated by loss of OCA2

  14. Acknowledgements The Ronald O. Perelman Department of Dermatology Dr. Prashiela Manga Dr. Seth J. Orlow Sponsors: Centers of Excellence Dysregulation of p53 in melanoma mediated by loss of OCA2

  15. Special thanks to: Dysregulation of p53 in melanoma mediated by loss of OCA2

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