UMGCC Research Program:
Experimental Therapeutics Program
Contact
Information:
Mailing Address:
BIOPARK 1 - 308
University of Maryland School of Medicine
Baltimore, MD 21201
Email:
gcarey@som.umaryland.edu
Phone:
410-706-8191
Fax:
410-706-8234
Research Interests:
My research interests are to continue to examine the mechanism of mIgM mediated cell growth arrest and death in B-cell lymphomas. These studies will illuminate our understanding of membrane IgM- (mIgM) mediated B-cell deletion. We established that inactivation of PI3K and its effectors were requisites for mIgM mediated-growth-arrest and apoptosis and that mIgD failed to permanently inactivate this signaling enzyme, thus, allowing the cells to escape from the death program. We are further exploring the roles of both positively and negatively regulated PI3K/Akt effectors. Positive examples: mTOR, p70S6K, Akt, beta catenin, CDK2; e.g.. Negative examples: GSK3-b, forkhead transcription factors, and the PI3K antagonist PTEN, in mediating the mIgM response.
Our present data also shows that Ras is a critical effector of not only primary B cell, but also of B-lymphoma survival. Ras is also an important mediator between the B cell receptor and PI3K and Ras signaling is also differentially regulated by mIgM and mIgD receptors. Thus, strong, sub-baseline depression of Ras activity (>60%) by mIgM and weak to transient sub-baseline depression of Ras by mIgD (<19%), is directly correlated with the ability of the former and not the latter to effect cell death. Active Ras appears to be a negative regulator of latent cellular programs that suppress mitochondrially driven oxidant release and apoptosis. Lastly, Ras also appears to be the central control point of two distinct signaling networks/modules in B lymphoma cells. This includes the canonical Ras/Raf/MEK/ERK signaling program and Ras/PI3K/(mTOR,p70S6K,Akt, CDK2). While the former appears to be an important anabolic enhancer, the latter is absolutely critical for cell growth, survival and cell cycle progression. We observe that mIgM receptor signaling drive the dissociation of Ras from PI3K and from Raf and affect the populating of lipid rafts by Ras:PI3K. We will also determine the role of the ITAM (immune based tyrosine activation motif) in regulating these dynamics. Our current efforts are focused on further exploring the role of Ras as a critical initial target of the B cell receptor, a major determinant of B-cell outcomes and a major contributor to tumor survival, growth and proliferation.
Publications:
Carey GB, Semenova E, Qi X, Keegan AD. (2007) IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway. Cell Res. 17(11):942-55.
Sears KT, Daino H, Carey GB. (2007) Reactive oxygen species-dependent destruction of MEK and Akt in Manumycin stimulated death of lymphoid tumor and myeloma cell lines. Int J Cancer. 122(7):1496-1505
Jiang-Jang Hao, Gregory B. Carey and Xi Zhan (2004) Syk-Mediated Tyrosine Phosphorylation is Required for the Association of HS1 With Lipid Rafts and BCR Signalasome Complex. (In Press, J Biol. Chem)
Gregory B. Carey, Laura Tonnetti and David W. Scott (2003). The Role of the PI3K Pathway in Anti-IgM Sensitive and Resistant B-cell Lymphomas: Failure to Disengage PI3K Pathway Signaling Confers Anti-IgM Resistance to Growth Arrest and Apoptosis in the CH12 B-Cell Lymphoma In: Molecular Mechanisms of Programmmed Cell Death. [Edited By Yufang Shi, J. Cidlowski, D. W. Scott, and Y. B. Shi, eds. Kluwer Academic], Plenum Publishers, New York
Carey, G.B. and Scott D.W. (2001) Role of phosphatidylinositol 3-kinase in anti-IgM- and anti-IgD-induced apoptosis in B cell lymphomas. J. Immunology 163(3): 1618-26
