Research Interest:

Calcium Signaling in Muscle Physiology and Tumorigenesis

Description of Research Activity:

Ion calcium, as a second messenger, plays an essential role in many cell processes including muscle contraction, cell proliferation, migration and apoptosis. Our research areas focus on Ca 2+ signaling in muscle and cancer cells. Particularly, we are interested in Store-Operated Ca 2+ Entry (SOCE), a pathway to allow extracellular Ca 2+ to cross the plasma membrane and to participate intracellular Ca 2+ mediated cellular events.

With several muscle specific proteins deficient mouse strains, we previously demonstrated that SOCE exists in skeletal muscle with important physiological functions. The activation of SOCE requires the adjacency of plasma membrane and sarcoplasmic reticulum (SR) membrane, the interaction between the Ca 2+ sensor docking at ER/SR and the Ca 2+ channel locating at plasma membrane, as well as the presence of ryanodine receptor. Our current effort is to understand the role of SOCE and the functions of SOCE related genes in muscle fatigue, muscle development and aging.

Malfunction of SOCE may also contribute to carcinogenesis, such as in prostate, colon and esophageal cancers. We have found that several key proteins in SOCE pathway are altered in those cancer cells. Our research here is to understand the molecular mechanisms underlying the perturbed Ca 2+ signaling and how the changes in SOCE affect cancer cell growth, migration and apoptosis.

The long-term goal of our research is to identify therapeutic targets to overcome muscle weakness in aged population and to reduce tumorigenesis in cancer patients. The experimental methods to accomplish our aims include molecular biology techniques and heterogeneous expression of eukaryotic genes, spectrofluorometer measurement of intracellular Ca 2+ and confocal microscopy live cell imaging of Ca 2+ and fluorescent protein-tagged molecules.

Selected Recent publications:

Pan Z , Damron D, Nieminen AL, Bhat MB , Ma J. Depletion of Intracellular Ca 2+ by Caffeine and Ryanodine Induces Apoptosis of Chinese Hamster Ovary Cells Transfected with Ryanodine Receptor. J. Biol. Chem. 2000; 275(26): 19978-19984

Pan Z , Bhat MB, Nieminen AL, Ma J. Synergistic movements of Ca 2+ and Bax in cells undergoing apoptosis. J. Biol. Chem. 2001; 276: 32257-32263

Pan Z , Yang D, Nagaraj RY, Nosek TA, Nishi M, Takeshima H, Cheng H, Ma J. Deletion of mg29 Gene Leads to Defective Function of Store-Operated Ca 2+ Channel in Skeletal Muscle. Nature Cell Biology . 2002; 4(5) 379-383

Ma J and Pan Z . Retrograde Activation of Store-Operated Calcium Channel. Cell Calcium . 2003, 33: 375–384 (review)

Pan Z , Hirata Y, Nagaraj RY, Zhao J, Nishi M, Hayek SM, Bhat MB, Takeshima H, Ma J. Co-expression of mg29 and ryanodine receptor leads to apoptotic cell death - effect mediated by intracellular Ca 2+ release. J. Biol. Chem. 2004; 279: 19387 - 19390 (accelerated publication)

Hirata Y, Brotto M, Weisleder N, Chu Y, Lin P, Zhao X, Thornton A, Komazaki S, Takeshima H, Ma J, Pan Z . Uncoupling of store-operated Ca 2+ entry through silencing of junctophilin genes. Biophysical J. 2006; 90(12): 4418-27

Cai C, Masumiya H, Weisleder N, Nishi M, Komazaki S, Ko JK, Lin P, Thornton A, Pan Z , Brotto M, Takeshima H and Ma J. Muscle membrane repair mediated by a TRIM family protein. Nature Cell Biology , 2009 11(1):56-64

Li N, Zheng L, Lin P, Danielpour D, Pan Z , Ma J. Overexpression of Bax Induces Down-Regulation of Store-Operated Calcium Entry in Prostate Cancer Cells. J. Cell. Physiology . 2008 216(1): 172-9

Cai C, Masumiya H, Weisleder N, Pan Z , Nishi M, Komazaki S, Takeshima H, Ma J. MG53 regulates membrane budding and exocytosis in muscle cells. J Biol Chem . 2009 284(5):3314-22

Calcraft PJ*, Ruas M*, Pan Z *, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature, 2009, 459: 596-601 *equal contribution

Zimering M, Pan Z . Auto-antibodies in type 2 diabetes induce stress fiber formation and apoptosis in endothelial cells. J Clin Endocrinol Metab , 2009, 94(6):2171-7