{"id":2298,"date":"2024-02-15T17:50:35","date_gmt":"2024-02-15T22:50:35","guid":{"rendered":"https:\/\/www.med.unc.edu\/pharm\/pruittlab\/?page_id=2298"},"modified":"2024-04-19T13:08:09","modified_gmt":"2024-04-19T17:08:09","slug":"research","status":"publish","type":"page","link":"https:\/\/www.med.unc.edu\/pharm\/pruittlab\/research\/","title":{"rendered":"Research"},"content":{"rendered":"

Pruitt lab research involves 3 broad areas. Interest in the first area (cancer epigenetics) stemmed from discoveries made during postdoctoral training assessing how tumor progression disrupts epigenetic mechanisms of control. The second area (Wnt pathway regulation) was the result of early screens as an Assistant Professor at LSU Health Sciences Center. We uncovered novel regulators of oncogenic Wnt signaling and published the first observation that epigenetic enzymes regulate a critical mediator of Wnt signaling (Dishevelled). The third project involves elucidating mechanisms of aromatase regulation which emerged from the obsession of early trainees in the lab with understanding mechanisms cancer-associated estrogen biosynthesis. Within the context of these three projects, I have mentored and guided multiple trainees at every level over the course of 17 years.<\/p>\n

Cancer epigenetics<\/h2>\n

FDA-approved \u201cepigenetic therapies\u201d exhibit anti-cancer activity but much remains unknown about their mechanisms of action. Because the epigenome of cancer cells within the tumor microenvironment (TME) directly impacts tumor progression, it is important to understand the regulation and contribution of epigenetic drivers. Research in the Pruitt lab is focused on understanding the mechanisms by which epigenetic readers, writers and erasers modulate oncogenic signaling and tumor growth. We seek to determine how tumor-intrinsic epigenetic changes contribute to tumor infiltrating leukocyte (TIL) recruitment in the TME.<\/p>\n

Wnt Signaling<\/h2>\n

Alterations in Wnt signaling drive pathologies ranging from developmental disorders to cancers. Wnt ligands activate Dishevelled (DVL) proteins which coordinate multiple Wnt signaling branches. Despite the critical role of DVL in Wnt signaling, its nuclear role remains an enigma. This second project seeks to define the role of cytosolic and nuclear DVL in cancer progression. We are elucidating the role of DVL family members in transcription of novel gene targets, especially those which could impact the recruitment of immune cells to the TME.<\/p>\n

\"Twenty<\/a>
DVL1 nuclear translocation is controlled by NLS and NES motifs.<\/b> Expression of DVL1 with wildtype (WT) or a mutant nuclear localization signal NLS (NLSm) or mutant nuclear export sequence (NESm) affect nuclear translocalization and retention in (A) MDA-MB-468 (B) and MDA-MB-231 breast cancer cells.<\/div><\/div>
\"Three<\/a>
Discovery of two lysines that control DVL1 nuclear localization.<\/b> (A) Schematic of DVL1 domains and two lysine acetylation sites (green) and the C-terminal region in which 14 different DVL1 mutations have been linked with Robinow Syndrome. Lysine acetylation was identified on several residues in DVL1. (B) Model for DVL1 interacting with transcription factors (TF) or other proteins at genomic loci. (C) Analysis of two sites revealed that the DIX (K69) and PDZ (K285) domain lysine controls DVL nuclear translocation. Two different aa K>R and K>Q show that these two residues act as a regulatory switch and affects DVL1 nuclear translocation in MDA-MB-468 breast cancer cells as well as several others tested (Sharma et al PMIDs 31700102, 34733415)<\/div><\/div>
\"24<\/a>
DVL3 nuclear translocation is controlled by NLS and NES motifs.<\/b> Expression of DVL3 with wildtype (WT) or a mutant nuclear localization signal NLS (NLSm) or mutant nuclear export sequence (NESm) affect nuclear translocalization and retention in (A) MDA-MB-468 (B) and MDA-MB-231 breast cancer cells.<\/div><\/div><\/div><\/div>\n

Cancer-associated estrogen biosynthesis<\/h2>\n

CYP19A1<\/em>\u00a0gene encodes aromatase which catalyzes the conversion of androgens to estrogens. Its dysfunctional regulation drives disparate pathologies ranging from autoimmune disorders and endometriosis to cancer. In screens for new mechanisms of transcriptional and post-translational regulation of aromatase, we identified new candidates. This third project seeks to characterize these new mechanisms of aromatase regulation.<\/p>\n

Publications<\/h2>\n

List of Dr. Pruitt’s publications in his NCBI Bibliography<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

Pruitt lab research involves 3 broad areas. Interest in the first area (cancer epigenetics) stemmed from discoveries made during postdoctoral training assessing how tumor progression disrupts epigenetic mechanisms of control. The second area (Wnt pathway regulation) was the result of early screens as an Assistant Professor at LSU Health Sciences Center. We uncovered novel regulators … Read more<\/a><\/p>\n","protected":false},"author":22429,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"layout":"","cellInformation":"","apiCallInformation":"","footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-2298","page","type-page","status-publish","hentry","odd"],"acf":[],"yoast_head":"\nResearch - Pruitt Lab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.med.unc.edu\/pharm\/pruittlab\/research\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Research - Pruitt Lab\" \/>\n<meta property=\"og:description\" content=\"Pruitt lab research involves 3 broad areas. 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