Zui Pan Assistant Professor UMDNJ Dept. of Physiology/Biophysics 683 Hoes Lane RWJMS Research Building. Room 157 Piscataway. NJ 08854 (732) 235-4509 FAX - 4483 panzu@umdnj.edu

Calcium Signaling in Muscle Physiology and Tumorigenesis

Ion calcium, as a second messenger, plays an essential role in many cell processes including muscle contraction, cell proliferation and apoptosis. My laboratory’s research interests focus on Ca2+ signaling in muscle physiology and tumorigenesis. Particularly, we study Store-Operated Ca2+ Entry (SOCE), a pathway to allow extracellular Ca2+ to pass the plasma membrane for replenishment of the depleted intracellular Ca2+ stores.

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 Ca2+ sensor docking at ER/SR and the Ca2+ channel locating at plasma membrane, as well as the presence of ryanodine receptor. Using microarray and RNA interfering techniques, we have identified co-factors for regulation of SOCE in muscles. Our current effort is to characterize the role of these genes in SOCE and to investigate their functions in muscle fatigue, muscle development and aging.

Alteration in SOCE not only causes muscle weakness but may also contribute to carcinogenesis, such as in prostate cancer and esophageal tumor cells. We have found that several key proteins in SOCE pathway are either down-regulated or up-regulated in those cancer cells. Our research here is to understand the molecular mechanisms underlying the perturbed Ca2+ signaling and how the changes in SOCE affects cancer cell growth, migration and apoptosis.

The long-term goal of our research is to identify a therapeutic target to overcome muscle weakness in aged population or 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 Ca2+ and confocal microscopy live cell imaging of Ca2+ and fluorescent protein-tagged molecules.

Selected Publications

Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Ko JK, Lin P, Thornton A, Zhao X, Pan Z, Komazaki S, Brotto M, Takeshima H, Ma J. (2008) MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol. Nov 30. [Epub ahead of print]

Cai C, Masumiya H, Weisleder N, Pan Z, Nishi M, Komazaki S, Takeshima H, Ma J. (2008) MG53 regulates membrane budding and exocytosis in muscle cells. J Biol Chem. Nov 24. [Epub ahead of print]

Pan Z, Harischandra DN, Newcomb M. (2008) Formation of stable and metastable porphyrin- and corrole-iron(IV) complexes and isomerizations to iron(III) macrocycle radical cations. J Inorg Biochem. Oct 10. [Epub ahead of print]

Li N, Zheng L, Lin P, Danielpour D, Pan Z, Ma J. (2008) Overexpression of Bax induces down-regulation of store-operated calcium entry in prostate cancer cells. J Cell Physiol. 216(1):172-9.

Li X, Pérez L, Pan Z, Fan H. (2007) The transmembrane domain of TACE regulates protein ectodomain shedding. Cell Res. 17(12):985-98.

Ko JK, Choi KH, Pan Z, Lin P, Weisleder N, Kim CW, Ma J. (2007) The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis. J Cell Sci. 120(Pt 16):2912-23.

Yazawa M, Ferrante C, Feng J, Mio K, Ogura T, Zhang M, Lin PH, Pan Z, Komazaki S, Kato K, Nishi M, Zhao X, Weisleder N, Sato C, Ma J, Takeshima H. (2007) TRIC channels are essential for Ca2+ handling in intracellular stores. Nature. 448(7149):78-82.

Landstrom AP, Weisleder N, Batalden KB, Martijn Bos J, Tester DJ, Ommen SR, Wehrens XH, Claycomb WC, Ko JK, Hwang M, Pan Z, Ma J, Ackerman MJ. (2007) Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol. 42(6):1026-35.

Hong M, Tanaka K, Pan Z, Ma J, You G. (2007) Determination of the external loops and the cellular orientation of the N- and the C-termini of the human organic anion transporter hOAT1. Biochem J. 401(2):515-20.

Zhao X, Weisleder N, Han X, Pan Z, Parness J, Brotto M, Ma J. (2006) Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor.
J Biol Chem. 281(44):33477-86.

Weisleder N, Brotto M, Komazaki S, Pan Z, Zhao X, Nosek T, Parness J, Takeshima H, Ma J. (2006) Muscle aging is associated with compromised Ca2+ spark signaling and segregated intracellular Ca2+ release. J Cell Biol. 174(5):639-45.

Xu C, Yuan X, Pan Z, Shen G, Kim JH, Yu S, Khor TO, Li W, Ma J, Kong AN. (2006) Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2.
Mol Cancer Ther. 5(8):1918-26.

Devadas S, Das J, Liu C, Zhang L, Roberts AI, Pan Z, Moore PA, Das G, Shi Y. (2006) Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity. 25(2):237-47.

Uzumcu M, Pan Z, Chu Y, Kuhn PE, Zachow R. (2006) Immunolocalization of the hepatocyte growth factor (HGF) system in the rat ovary and the anti-apoptotic effect of HGF in rat ovarian granulosa cells in vitro. Reproduction. 132(2):291-9.

Yuan X. Xu C. Pan Z. Keum YS. Kim JH. Shen G. Yu S. Oo KT. Ma J. Kong AN. (2006) Butylated hydroxyanisole regulates ARE-mediated gene expression via Nrf2 coupled with ERK and JNK signaling pathway in HepG2 cells. Mol Carcinog. 45(11):841-50.

Cai C. Lin P. Cheung KH. Li N. Levchook C. Pan Z. Ferrante C. Boulianne GL. Foskett JK. Danielpour D. Ma J. (2006) The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem. 281(24):16649-55.

Hirata Y. Brotto M. Weisleder N. Chu Y. Lin P. Zhao X. Thornton A. Komazaki S. Takeshima H. Ma J. Pan Z. (2006) Uncoupling store-operated Ca2+ entry and altered Ca2+ release from sarcoplasmic reticulum through silencing of junctophilin genes. Biophys J. 90(12):4418-27.

Ju J. Hong J. Zhou JN. Pan Z. Bose M. Liao J. Yang GY. Liu YY. Hou Z. Lin Y. Ma J. Shih WJ. Carothers AM. Yang CS. (2005) Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate. the major catechin in green tea. Cancer Res. 65(22):10623-31.

Wang X. Weisleder N. Collet C. Zhou J. Chu Y. Hirata Y. Zhao X. Pan Z. Brotto M. Cheng H. Ma J. (2005) Uncontrolled calcium sparks act as a dystrophic signal for mammalian skeletal muscle. Nat Cell Biol. 7(5):525-30.

Lin PH. Pan Z. Zheng L. Li N. Danielpour D. Ma JJ. (2005) Overexpression of Bax sensitizes prostate cancer cells to TGF-beta induced apoptosis. Cell Res. 15(3):160-6.

Zhou F. Xu W. Hong M. Pan Z. Sinko PJ. Ma J. You G. (2005) The role of N-linked glycosylation in protein folding. membrane targeting. and substrate binding of human organic anion transporter hOAT4. Mol Pharmacol. 67(3):868-76.

Zhou F. Pan Z. Ma J. You G. (2004) Mutational analysis of histidine residues in human organic anion transporter 4 (hOAT4). Biochem J. 384(Pt 1):87-92.

Zhou F. Tanaka K. Pan Z. Ma J. You G. (2004) The role of glycine residues in the function of human organic anion transporter 4. Mol Pharmacol. 65(5):1141-7.

Pan. Z.. Hirata. Y.. Nagaraj. R.Y.. Zhao. J.. Nishi. M.. Hayek. S.. Bhat. M.B.. Takeshima. H. and Ma. J. (2004) Co-expression of mg29 and ryanodine receptor leads to apoptotic cell death - effect mediated by intracellular Ca release. J. Biol. Chem. 279: 19387-19390.

Nur-E-Kamal. A.. Gross. S.R.. Pan. Z.. Balklava. Z.. Ma. J. and Liu. L.F. (2004) Nuclear translocation of Cytochrome c during apoptosis. J. Biol. Chem. 279: 19387 - 19390.

Brostrom. M. . Pan. Z.. Meiners. S.. Drumm. C.. Ahmed. I. and Brostrom. C.O. (2003) Ca2+ dynamics of thrombin-stimulated rat heart-derived embryonic myocytes: relationship to protein synthesis and cell growth. International J. Biochemistry Cell Biol. 35: 1573-1587.

Shin. D.W.. Pan. Z.. Kim. E. K.. Lee. J. M.. Bhat. M.. Parness. J.. Kim. D.H. and Ma. J. (2003) A retrograde signal from Calsequestrin for the regulation of store-operated Ca2+ entry in skeletal muscle. J. Biol. Chem. 278 (5): 3286-3292.

Ma. J. and Pan. Z. (2003) Junctional membrane structure and store operated calcium entry in muscle cells. Frontier in Bioscience. 8 (1): 242-255 (review article)

Ma. J. and Pan. Z. (2003) Retrograde activation of store-operated calcium channel in muscle cells. Cell Calcium. 33: 375-384 (review article)

Pan. Z.. Yang. D.. Nagaraj. R.Y.. Nosek. M. Nishi. H. Takeshima. H. Cheng. H. and Ma. J. (2002) Dysfunction of store-operated Ca2+ channel in muscle cells lacking mg29 gene. Nature Cell Biology 4(5):379-383.

Shin. D.W.. Pan. Z.. Bandyopadhyay. A.. Bhat. M.. Kim. D.H. and Ma. J. (2002) Calcineurin-dependent dephosphorylation of ryanodine receptor down-regulates activity of the Ca2+ release channel in skeletal muscle. Biophys. J.83 (11): 2539-2549.

Pan. Z.. Bhat. M.B.. Nieminen. A.-L. and Ma. J. (2001) Synergistic movements of Ca2+ and Bax in cells undergoing apoptosis. J. Biol. Chem. 276:32257-63.

Yang. D.. Pan. Z.. Takeshima. H.. Wu. C.. Nagaraj. R.Y.. Ma. J. and Cheng. H. (2001) RyR3 amplifies RyR1-mediated Ca2+-induced Ca2+ release in neonatal mammalian skeletal muscle. J. Biol. Chem. 276:40210-14.

Pan. Z.. Damron. D.. Nieminen. A-L.. Bhat. M.B. and Ma. J. (2000) Depletion of intracellular Ca2+ by caffeine and ryanodine induces apoptosis of chinese hamster ovary cells transfected with ryanodine receptor. J. Biol. Chem. 275(26): 19978-19984.