Baldwin Lab

Baldwin Lab

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The Baldwin Lab is a part of the UNC Lineberger Comprehensive Cancer Center, an NCI designated Cancer Center associated with the UNC School of Medicine and the University of North Carolina at Chapel HillOur laboratory focuses on the regulation and biological functions of the transcription factor NF-kappaB and on the role of NF-kappaB in disease, with a particular emphasis on cancer and cancer therapy. These studies focus on the signaling pathways which target NF-kappaB, on the biological mechanisms which NF-kappaB controls, and on the ability of NF-kappaB to promote basic oncogenic mechanisms as well as resistance to cancer therapy.

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Research

NF-κB ActivationThe laboratory continues to focus on the regulation and biological functions of the transcription factor NF-kappaB and on the role of NF-kappaB in disease, with a particular emphasis on cancer and cancer therapy. These studies focus on the signaling pathways which target NF-kappaB, on the biological mechanisms which NF-kappaB controls, and on the ability of NF-kappaB to promote basic oncogenic mechanisms as well as resistance to cancer therapy.
 

Recent Accomplishments

  1. NF-kB and control of cell growth and suppression of differentiation. We have shown that NF-kB promotes cell proliferation through the direct transcriptional regulation of the cyclin D1 promoter (published in Molecular and Cellular Biology). We have studied the link between cell growth and suppression of cell differentiation. Our data indicate that the activation of NF-kB in myoblasts suppresses the ability of these cells to differentiate into myofibers. The mechanisms for this suppression of differentiation comes from the ability of activated NF-kB to lead to the loss of the mRNA encoding MyoD. MyoD is the key transcription factor involved in muscle differentiation. Results in this paper indicated that the loss of MyoD mRNA induced by NF-kB occurred at a post-transcriptional level. This work was published in Science. Importantly, we have now found that another key transcription factor which controls differentiation of chondrocytes (Sox9) is lost by a similar mRNA-dependent mechanism (in press, Genes and Development). This study revealed that common motifs in the MyoD and Sox9 mRNAs control the NF-kB-dependent RNA loss. It is important to consider that the activation of NF-kB in certain cancers may inhibit tumor cell differentiation and, in this regard, we have begun the analysis of mRNAs that are downregulated in an NF-kB-dependent manner in certain cancers.
  2. Role of oncoprotein Bcl-3 in cell growth and oncoenesis. We have found that the IkB homologue Bcl-3 (cloned based on a translocation in certain leukemias) interacts with the NF-kB p52 subunit to strongly upregulate cyclin D1 gene transcription and to promote G1/S transition. This paper was published in Molecular and Cellular Biology. We believe that these findings are very important as previously we had described that Bcl-3 and p52 are upregulated in breast tumors (published in Oncogene) and it is known that cyclin D1 is also upregulated in breast cancer and may be required for tumor progression (at least in certain models). New experiments in the laboratory are focused on the potential involvement of Bcl-3 in controlling p53 function.
  3. Oncoprotein signaling and NF-kB: Ras- and BCR-ABL-induced pathways and NF-kB. We have previously shown that oncogenic Ras and oncogenic Raf activate NF-kB functional activity and that NF-kB is required for Ras to induce cellular transformation. Importantly we have shown that BCR-ABL requires Ras to induce NF-kB activation and that NF-kB is required for BCR-ABL to induce tumorigenesis (this paper was publised in Genes and Development and was the first to show the requirement of NF-kB in tumor formation). We have shown that Akt (downstream of the Ras effector PI3K) activates NF-kB through a mechanism independent of induced nuclear accumulation but dependent on the enhancement of inherent transcriptional potential (stimulating transactivation function). This process involves the IkB kinase, which is surprising since IKK was thought only to function to promote nuclear accumulation of NF-kB. This work was published at J. Biol. Chem. Another paper recently published in J. Biol. Chem. shows that Ras suppresses the traditional activation of NF-kB as induced by TNF (but not IL-1) while simultanenously promoting the activation of NF-kB-dependent gene expression. This work indicates that Ras induces NF-kB functional through a pathway which does not utilize the upstream signaling pathways associated with cytokine induction. The results also suggest the potential that Ras suppresses TNF induction of NF-kB in order to promote the chronic upregulation of JNK. In fact, we have published (Molecular and Cellular Biology) that NF-kB suppresses persistent JNK activation.
  4. NF-kB and suppression of apoptosis: new therapeutic approaches for cancer therapy. We have published in a series of papers (Science, Molecular and Cellular Biology) that NF-kB activation strongly blocks apoptosis through the upregulation of specific anti-apoptotic genes. We published in Nature Medicine that the inhibition of NF-kB through a gene therapy approach strongly sensitized tumors to chemotherapy. Furthermore, we have published in Cancer Research that systemic chemotherapy plus systemic NF-kB inhibition (with PS-341) strongly synergize to promote tumor cell apoptosis. Additionally, we have shown that thalidomide is a potent inhibitor of NF-kB (published at J. Biol. Chem.) and we have now data that thalidomide synergizes with chemotherapy in causes tumor regression through enhanced apoptosis.
  5. NF-kB and chromatin: novel findings regarding the involvement of IKK in controlling chromatin/histone modification. A paper from the laboratory was published in Molecular and Cellular Biology showing that NF-kB associates functionally with histone deacetylase proteins (HDAC1 and 2) and that NF-kB can actively promote transcriptional repression. Thus, NF-kB can both repress or activate gene expression according to promoter and inducer specificity. Recently, we published in Nature that the IKKa subunit of IKK associates with NF-kB-regulated promoters to control the phosphorylation of histone H3 on ser10. This finding is a key result in dissecting the factors which control modification of chromatin (according to the histone code hypothesis) to regulate gene expression. These studies are now being extended to determine a role of IKKa in controlling EGF-induced gene expression and the associated control of oncogenesis through EGF receptor family members.

People

Prinicipal Investigator

Al Baldwin JrAlbert S. Baldwin, PhD - Principal Investigator
Kenan Professor of Biology and Cancer Cell Biology
Associate Director of Basic Research, UNC Lineberger
Postdoc, Sharp Lab, MIT
PhD, University of Virginia
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Postdocs

Cortney Lawrence


Cortney Lawrence, PhD - Postdoctoral Fellow
PhD, Virginia Commonwealth University


Sara Conard


Sara Conard, PhD - Postdoctoral Fellow
PhD, University of Alabama at Birmingham



Graduate Students

Amanda Rinkenbaugh


Amanda Rinkenbaugh - Molecular & Cellular Pathology
BS, University of Oklahoma
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Hung-Ching Hsia


Hung-Ching Hsia - Cell & Developmental Biology
MS, North Carolina State University
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Joel Durand


Joel Durand - Genetics & Molecular Biology
BS, Grambling State University
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Matthew Tegowski


Matthew Tegowski - Genetics & Molecular Biology
BS, Ohio State University
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Ricardo Antonia


Ricardo Antonia - Genetics & Molecular Biology
BS, University of Florida
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Research Assistants

Aaron Ebbs


Aaron Ebbs - Lab Manager
MS, University of Akron
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 Debanjali Kundu


Debanjali Kundu - Research Assistant
Undergrad, University of North Carolina
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Alumni

Postdocs

Jennifer Bradford, PhD - Postdoctoral Fellow
PhD, Emory University
Next: Assistant Professor, Georgia Regents University

Daniela Basseres, PhD - Postdoctoral Fellow
PhD, University of Campinas, Brazil
Next: Assistant Professor, Universidade de São Paulo

Hancai Dan, PhD - Postdoctoral Fellow
PhD, University of South Florida
Next: Assistant Professor, University of Maryland

Jessica Hutti, PhD - Postdoctoral Fellow
PhD, Harvard University
Next: Senior Scientist, Abbott

Raeshell Sweeting, MD - Clinical Fellow
MD, New York University
Next: Surgical Fellow, UNC Hospitals

Megan Kendellen, PhD Postdoctoral Fellow
PhD, Duke University
Next: Senior Clinical Project Support Specialist, Quintiles

Brian Bednarski, MDClinical Fellow
MD, Georgetown University Medical Center
Next: Surgical Oncology Fellow, MD Anderson Cancer Center


Graduate Students

Deepali Bang - Cell & Developmental Biology
MS, University of Delhi, India
PhD, 2014
Next: ...

Sarah Stein - Biology
BS, University of Massachusetts Amherst
PhD, 2013
Next: Postdoc, Pear Lab, University of Pennsylvania

Matthew Cooper - Genetics & Molecular Biology
BA, Lewis & Clark College
PhD, 2012
Next: Postdoc, Graves Lab, University of North Carolina 

William Comb - Genetics & Molecular Biology
BS, Boston University
PhD, 2011
Next: Postdoc, Sabatini Lab, Whitehead Institute

Evan Merkhofer - Genetics & Molecular Biology
BS, Gettysburg College
PhD, 2010
Next: Postdoc, Johnson Lab, University of California, San Diego

Willie Wilson III - Genetics & Molecular Biology
MS, North Carolina Central University
PhD, 2009
Next: Postdoc, Dennis Lab, National Cancer Institute


Research Assistants

Jose Roques - Research Technician
BS, Interamerican University of Puerto Rico
Next: Research Technician, Mouse Phase One Unit

Patty Cogswell - Lab Manager
MS, University of Rochester
Next: Manager of Research, Chordoma Foundation

Sean RussellResearch Technician
BS, East Carolina University
Next: Physician Assistant Program, East Carolina University

Pat TompkinsResearch Technician
BS, SUNY Buffalo
Next: Operations Manager, Summerfield Farms


Undergraduates

Shraddha Venkateswaran - Research Assistant
Undergrad, University of North Carolina

Mayukh Sircar - Research Assistant
Undergrad, University of North Carolina

Justina Chen - Research Assistant
Undergrad, University of North Carolina

Caroline Hill - Research Assistant
Undergrad, University of North Carolina

Contact

Albert S Baldwin, PhD - Principal Investigator
22-000 Lineberger Comprehensive Cancer Center
Tel.  919-966-3652
Fax. 919-966-8212
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Laboratory Address
University of North Carolina at Chapel Hill
21-210 Lineberger Comprehensive Cancer Center, CB# 7295
450 West Drive
Chapel Hill, NC 27599
Tel. 919-966-3884 or 919-966-6928

Calendar

Lab Meeting Schedule:
1. Ricky ... 2. Cortney ... 3. Matt ... 4. Joe ... 5. Amanda ... 6. Gloria ... 7. Sara