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Ming-Fong Lin
Professor, Biochemistry and Molecular Biology and Eppley Institute for Cancer
Ph.D., State University of New York, Buffalo, 1983
Office: DRC I, Room 7046
Phone: (402) 559-6658
Fax: (402) 559-6650
Email: mlin@unmc.edu
Click here for biographical sketch and further publications.
Tyrosine phosphorylation and Redox signal transduction in androgen regulation of cell proliferation and carcinogenesis.
Our current effort is to investigate the molecular mechanism of cell growth regulation via tyrosine phosphorylation and Redox signal transduction mediating androgen action for understanding one mechanism of multi-step carcinogenesis of prostate epithelium.
Protein tyrosine phosphorylation by several oncogene proteins and growth factor receptors has been well documented to play a crucial role in the control of cell growth. This is a cyclical process of regulation including phosphorylation and dephosphorylation, which can be regulated at either step. To delineate this cyclical regulatory mechanism, we examine the putative function and regulation of the cellular form of human prostatic acid phosphatase (PAcP), a prostate epithelium-specific protein tyrosine phosphatase. This is because PAcP expression can be regulated by androgens, which is a risk factor for prostate carcinogenesis. Our results show that the expression of cellular PAcP correlates with the androgen responsiveness of human prostate cancer cells. In those cells, cellular PAcP dephosphorylates HER-2/c-ErbB-2/neu proto oncoprotein at specific phosphotyrosine residues. Thus, the interaction of cellular PAcP and ErbB-2 regulates androgen sensitivity of prostate cells. Our recent data further reveal that Redox signaling is mediating the non-genomic androgen stimulated cell proliferation, in part via protein tyrosine phosphorylation signaling. By delineating the molecular mechanism of the cross-talks by tyrosine phosphorylation and Redox signaling mediating androgen action, we will obtain information necessary for a better understanding in some aspects of androgen effects on prostate cancer biology.
To investigate the molecular changes during the progression of prostate cancer cells from androgen-sensitive to advanced androgen-insensitive stages, we have established a U.S. patent-awarded cell model system that recapitulates clinical tumor progression. This model system would allow us to elucidate the molecular mechanism of cancer progression, leading to developing targeted therapies. For immediate clinical applications, we also pursue the development of novel therapeutic approaches applicable for the cases refracatory to hormonal therapy of the advanced cancer.
RECENT PUBLICATIONS:
Mimeault, M, Moore, E, Moniaux, N, Henichart, J-P, Depreux, P, Lin, M-F, and Batra, SK. (2006). Cytotoxic effects induced by a combination of Cyclopamine and Gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int. J. Cancer 118: 1022-1031. Abstract
Singh, AP, Chauhan, SC, Bafna, S, Johansson, SL, Smith, LM, Moniaux, N, Lin, M-F, and Batra, SK. (2006). Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas. The Prostate 66:421-429. Abstract
Yuan, TC, Veeramani, S, Lin, FF, Kondrikou, D, Zelivianski, S, Igawa, T, Karan, D, Batra, SK, and Lin, M-F. (2006). Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocrine-Related Cancer 13:151-167. Abstract
Cao, X, Qin, J, Xie, Y, Khan, O, Dowd, F, Scofield, M, Lin, M-F, and Tu, Y. (2006). Regulator of G-protein Signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene 25:3719-3734. Abstract
Mimeault, M, Venkatraman, G, Johansson, SL, Moore, E, Henichart, J-P, Depreux, P, Lin, M-F, and Batra, SK. (2006). Novel combination therapy against metastatic and androgen-independent prostate cancer forms by using a combination of Gefitinib, Tamoxifen and Etoposide. International J. Cancer 120:160-169. Abstract
Cai, C, Chen, S-Y, Zheng, Z, Omwancha, J, Lin, M-F, Balk, S-P, Shemshedini, L. (2006). Androgen regulation of soluble guanylyl cyclase α1 mediates prostate cancer cell proliferation. Oncogene 26:1606-1615. Abstract
Chen, SJ, Karan, D, Johansson, SL, Lin, F-F, Zeckser, J, Singh, AP, Batra, SK, and Lin,
M-F (2007). Prostate-derived factor as a paracrine and autocrine factor for the
proliferation of androgen receptor-positive human prostate cancer cells. The Prostate 67:557-571. Abstract
Mimeault, M, Johansson, SL, Venkatraman, G, Moore, E, Henichart, J-P, Depreux, P,
Lin, M-F., and Batra, S.K. (2007). Combined targeting of epidermal growth factor receptor
and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the
cytotoxic effects of docetaxel on metastatic prostate cancer cells. Mol. Cancer Ther.
6:967-978. Abstract
Xie, Y, Wolff, DW, Lin, MF, and Tu, Y (2007). Vasoactive intestinal peptide
transactivates the androgen receptor through a PKA-dependent extracellular signal-
regulated kinase pathway in prostate cancer LNCaP cells. Molecular Pharmacology 72:73-85. Abstract
Yuan, T-C, Lin, F-F, Veeramani, S, Chen, SJ, Earp, HS III, and Lin, M-F (2007). ErbB-
2 via PYK2 up-regulates the adhesive ability of androgen receptor-positive human
prostate cancer cells. Oncogene 26:7552-7559. Abstract
Yuan, T-C, Veeramani, S, and Lin, M-F (2007). Neuroendocrine-like prostate cancer
cells: Neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocrine- Related Cancer 14:531-547. Abstract
Mimeault, M, Mehta, PP, Hauke, R, Henichart, J-P, Depreux, P, Lin, M-F, and Batra, SK (2007). Improvement of cytotoxic effects induced by mitoxantrone on metastatic prostate cancer cells by co-targeting epidermal growth factor receptor and hedgehog signaling cascades. Growth Factors 25:400-416. Abstract
Singh, AP, Bafna, S, Chaudhary, K, Venkatraman, G, Smith, L, Eudy, JD, Johansson, SL, Lin, MF, and Batra, SK (2008). Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. Cancer Letters 259:28-38. Abstract
Veeramani, S, Yuan, TC, Lin, FF, and Lin, MF (2008). Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells. Oncogene 2008; 27:5057-5068. Abstract
Dillard, PR, Lin, MF, and Khan, SA (2008). Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol 2008 August 20 (E-pub ahead of print). Abstract
Ye CJ, Stevens JB, Liu G, Bremer SW, Jaiswal AS, Ye KJ, Lin MF, Lawrenson L, Lancaster WD, Kurkinen MK, Liao JD, Gairola CG, Shekhar MP, Narayan S, Miller FR, Heng HH. Genome based cell population heterogeneity promotes tumorigenicity: The evolutionary mechanism of cancer. J Cell Physiol 2008 Dec 29 (E-pub ahead of print). Abstract
Radhakrishnan P, Lin MF, Cheng PW. Elevated expression of L-selectin ligand in lymph node-derived human prostate cancer cells correlates with increased tumorigenicity. Glycoconj J. 26(1):75-81, 2008. Abstract
Alam S, Rajendran M, Ouyang S, Veeramani S, Li Z, Lin MF. A novel role of shc adaptor proteins in steroid hormone-regulated cancers. Endocr Relat Cancer. 2008. Abstract
Zhang L, Davis JS, Zelivianski S, Lin FF, Schutte R, Davis TL, Hauke R, Batra SK, Lin MF. Suppression of ErbB-2 in androgen-independent human prostate cancer cells enhances cytotoxic effect by gemcitabine in an androgen-reduced environment. Cancer Lett. 2009 May 23 [Epub ahead of print] Abstract
Veeramani S, Lee MS, Lin MF. Revisiting histidine-dependent acid phosphatases: A distinct group of tyrosine phosphatases. Trends Biochem Sci. 2009. Abstract
Qin J, Xie Y, Wang B, Hoshino M, Wolff DW, Zhao J, Scofield MA, Dowd FJ, Lin MF, Tu Y. Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene. 28(16):1853-63. Abstract
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