BBS Faculty Member - Nika Danial

Nika Danial

Department of Cell Biology

Dana Farber Cancer Institute
Center for Life Sciences Building 11-143
3 Blackfan Circle
Boston, MA 02115
Tel: 617-632-6436
Fax: 617-632-5363
Email: nika_danial@dfci.harvard.edu
Visit my lab page here.



The primary focus of our laboratory is to delineate cellular energy and nutrient sensing pathways, including metabolic checkpoints that integrate cellular survival and bioenergetics. We use multi-disciplinary approaches including, mouse models, mitochondrial bioenergetics, systemic physiology, chemical biology, proteomics and metabolomics to identify key metabolic pathways that determine the cell’s response to physiologic and pathophysiologic stress. Within this framework, our studies show that pathways controlling the cell’s choice of fuel substrates, for example glucose vs. non-glucose substrate utilization are important modulators of stress responses and can be used to uncover potential targets in diseases such as cancer, diabetes and seizure disorders.

We have recently discovered that BAD, a BCL-2 family protein best known for its apoptotic function, has an alternative role in reciprocal programming of glucose vs. fatty acids and ketone body metabolism. BAD’s functional modalities in metabolism and apoptosis are cued by nutrient sensing pathways and survival/death signaling networks that ultimately influence BAD’s phosphorylation on serine 155 within an alpha helical segment known as the BCL-2 homology (BH)-3 domain. Serine 155 phosphorylation is required for mitochondrial metabolism of glucose while it suppresses fatty acid and ketone body oxidation. When serine 155 is dephosphorylated, metabolism of glucose is blunted while that of fatty acid and ketone bodies is activated. In the presence of apoptotic signals, including irreversible cellular damage, dephosphorylated BAD can engage the mitochondrial apoptosis machinery through a BH3 domain dependent mechanism that sensitizes cells to apoptotic demise. The implications of BAD’s dual functions in metabolism and apoptosis as well as BAD-dependent reprogramming of fuel metabolism are the basis of several ongoing projects. These include metabolic control of neuronal excitation under physiological conditions and in seizure disorders, coordinate programming of hepatic energy and nutrient metabolism in fed and fasted states, and glucose regulation of beta-cell survival and insulin secretion in normal physiology and in diabetes. We are also using molecular approaches to assess how cellular metabolic cues, alone or parallel to other signaling pathways regulate BAD phosphorylation to integrate carbon substrate utilization and cellular stress outcomes.

In addition to BAD-dependent modulation of fuel metabolism, we are exploring other signaling pathways in charge of cellular fuel choice. For example, we have recently shown that in Diffuse Large B-cell Lymphoma (DLBCL), which consists of tumor subtypes with distinct genetic signatures, activation of distinct fuel utilization pathways can be linked to signaling downstream of the B-Cell receptor (BCR). We are currently dissecting the molecular connection between BCR signaling and the choice of fuel substrates. These studies will help define points of metabolic vulnerabilities that can be potentially used for target discovery in these tumors.



Last Update: 5/28/2013



Publications

For a complete listing of publications click here.

 


 

Danial NN, Walensky LD, Zhang C-Y, Choi CS, Fisher JK, Molina A, Datta SR, Pitter K, Bird GH, Wikstrom JD, Deeney JT, Robertson K, Morash J, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB, Korsmeyer SJ. Dual role of pro-apoptotic BAD in insulin secretion and beta cell survival. Nat Med 14:144-53, 2008.

Roy, S.S., Madesh, M., Davies, E., Antonsson, B., Danial, N.N., and Hajnoszky, G. Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death.
Mol. Cell.33:377-88, 2009.

Osundiji, M.A., Godes, M., Evans, M.L., and Danial, N.N. BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding,
PLoS ONE 6:e28016, 2011.

Gimenez-Cassina A, Ramón Martínez-François J, Fisher JK, Szlyk B, Polak K, Wiwczar J, Tanner GR, Lutas A, Yellen G, Danial NN. BAD-dependent regulation of fuel metabolism and KATP channel activity confers resistance to epileptic seizures.
Neuron.74:719-30, 2012.

Caro P, Kishan AU, Norberg E, Stanley I, Chapuy B, Ficarro SB, Tondera D, Polak K, Gounarides, J, Yin H, Green M, Chen L, Monti S, Marto JA, Shipp MA, Danial NN. Metabolic signatures uncover distinct targets in diffuse large B-cell lymphoma.
Cancer Cell, accepted



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