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dc.contributor.advisorFisher, David Erich
dc.contributor.authorVeguilla, Rosa Angelica
dc.date.accessioned2013-02-08T15:29:17Z
dash.embargo.terms2014-06-21en_US
dc.date.issued2013-02-08
dc.date.submitted2012
dc.identifier.citationVeguilla, Rosa Angelica. 2012. Transcriptional Regulation of OCA2 and POMC by a cAMP-Dependent Mechanism and Implications in Skin Pigmentation. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:10095en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10288431
dc.description.abstractSkin Pigmentation represents the major natural protection against the deleterious effects of Ultraviolet light and involves a crosstalk between keratinocytes and melanocytes. Pigment synthesis or melanogenesis is initiated by the binding of \(\alpha\)-Melanocyte Stimulating Hormone \((\alpha-MSH)\) to the Melanocortin 1 Receptor (MC1R), expressed by the melanocytes. α-MSH is generated by cleavage of pro-opiomelanocortin hormone (POMC), produced by both melanocytes and keratinocytes. Activation of MC1R leads to an increase in cAMP levels, causing the expression of the transcription factor MITF. MITF regulates the expression of the enzymes involved in melanogenesis as well as genes important for the survival and proliferation of melanocytes. Pigment synthesis, which occurs in specialized organelles called melanosomes, involves the regulation of different proteins as well as fine homeostatic tuning such as melanosomal pH regulation. The POMC derivative, \(\alpha-MSH\), begins the pigmentation pathway by activating the MC1R signaling pathway, and OCA2 regulates the end of this pathway by controlling tyrosinase activity. The OCA2 gene has been shown to be important in the control of intra-melanosomal pH to allow optimal conditions for the activity of Tyrosinase, the limiting enzyme of pigment (melanin) production. OCA2 polymorphisms have been linked to oculocutaneous albinism type 2 and to blue eye color, demonstrating the importance of this gene in fine pH regulation on pigment production. Polymorphisms in POMC have also been linked to red-haired/fair-skin color in humans. Despite the effort to dissect the mechanisms involved in the control of pigmentation, the transcriptional regulation of POMC and OCA2 are still not fully understood. In this study, we investigate the relevance of the cAMP/CREB pathway in the transcriptional regulation of these two proteins. Our data shows that both POMC and OCA2 expression increases after stimulation of the cAMP/CREB pathway. We demonstrate that MITF transcriptionally regulates OCA2: the cAMP/CREB pathway therefore induces OCA2 in a MITF-dependent manner. On the other hand, our data reveals that POMC may be regulated by cAMP in a MITF-independent fashion but consistent with the hypothesis of a positive feedback loop within the MC1R signaling pathway.en_US
dc.language.isoen_USen_US
dash.licenseMETA_ONLY
dc.subjectmelanosomesen_US
dc.subjectMITFen_US
dc.subjectOCA2en_US
dc.subjectpHen_US
dc.subjectpigmentationen_US
dc.subjectPOMCen_US
dc.subjectmolecular biologyen_US
dc.subjectbiochemistryen_US
dc.subjectbiologyen_US
dc.titleTranscriptional Regulation of OCA2 and POMC by a cAMP-Dependent Mechanism and Implications in Skin Pigmentationen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorVeguilla, Rosa Angelica
dash.embargo.until10000-01-01
thesis.degree.date2012en_US
thesis.degree.disciplineBiochemistryen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberVerdine, Gregoryen_US
dc.contributor.committeeMemberFrancis, Nicoleen_US
dc.contributor.committeeMemberHaigis, Kevinen_US
dash.contributor.affiliatedVeguilla, Rosa Angelica


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