Publications

List of key publications from the Fiscus Lab highlighting research accomplishments.

Publications (from a total of 88 Peer-reviewed research articles, 8 book chapters, ~100 scientific presentations):

Early scientific articles by Dr. Fiscus contributing to the 1998 Nobel Prize in Physiology or Medicine

(from a total of 10 publications with Dr. Ferid Murad, 1998 Nobel Laureate, based on research conducted in Dr. Murad's lab at Stanford University School of Medicine & Palo Alto VA Medical Center, 1983 - 1985, and some early research conducted in the R.R. Fiscus Lab at Loyola University of Chicago, Stritch School of Medicine, 1985 - 1990):

Fiscus RR, Rapoport RM, Murad F (1983-1984) Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta. J Cyclic Nucleotide Protein Phosphor Res 9: 415-425.

First publication to establish that nitric oxide (NO) activates the novel protein kinase, cyclic GMP-dependent protein kinase [now called protein kinase G (PKG)] in biological samples [in this case, vascular smooth muscle cells (VSMCs)] and to show that PKG mediates the biological response to NO, i.e. vasorelaxation and anti-hypertensive effects. The PKG activation in VSMCs was caused by either therapeutically-derived NO, released from sodium nitroprusside (powerful anti-hypertensive agent), or from endothelial cells, in close proximity to the VSMCs, exposed to cholinergic stimulation (e.g. acetylcholine). Importantly, this publication was the first to show a modest, but statistically-significant, elevation of the catalytic/kinase activity of PKG within VSMCs by simply the presence of nearby unstimulated endothelial cells (if healthy, i.e. not from diabetic animals and not exposed to high glucose or high lipids), thus establishing that even basal production of NO by the eNOS in healthy endothelial cells is sufficient to modestly elevate PKG kinase activity in the nearby cells. This laid the foundation for the current concept that eNOS in endothelial cells is continuously providing "healthy-level" NO to nearby cells, such as brain neural cells, pancreatic beta-cells and stem cells (i.e. providing "stem cell niche") to activate their PKG (now recognized to be specifically the PKG-I-alpha splice variant), which provides an essential role to promote cell survival and healthy function.

Fiscus RR, Rapoport RM, Waldman SA, Murad F (1985) Atriopeptin II elevates cyclic GMP, activates cyclic GMP-dependent protein kinase and causes relaxation in rat thoracic aorta. Biochim Biophys Acta 846: 179-184.

First paper to show that atrial natriuretic peptide (ANP) elevates the catalytic/kinase activity of PKG in biological tissues [in this case, vascular smooth muscle cells (VSMCs)], resulting in vasodilation and anti-hypertensive effects. It is now recognized that ANP and other more-recently discovered natriuretic peptides [e.g. brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP)] can all stimulate the kinase activity of PKG in many different types of cells/tissues, including pancreatic beta-cells (see our 2017 publication), neural cells (Fiscus Lab publications 2001-present) and bone marrow-derived mesenchymal stem cells (BM-MSCs) (see our 2011 and 2017 publications). In all of these cell types, ANP and other natriuretic peptides promote the cell survival and regeneration via their ability to stimulate the kinase activity of the PKG-I-alpha splice variant of PKG (see publications below and the Models in the Research section). In addition to the heart, BM-MSCs are now known to synthesize and released ANP and BNP, which serve as stem-cell-derived cytoprotective/regeneration factors that promote the cell survival and regeneration of nearby cells. As an example, we recently showed that ANP released from nearby BM-MSCs promote the cell survival and proliferation of insulin-producing pancreatic beta-cells via the stimulating of PKG-I-alpha kinase activity and its downstream phosphorylation/regulation of Akt, FoxO1 and PDX-1 (Wong, Vo, Gorjala & Fiscus, 2017).

Murad F, Rapoport RM, Fiscus RR (1985) Role of cyclic GMP in relaxations of vascular smooth muscle. J Cardiovasc Pharmacol 7 Suppl 3:S111-S118.

Fiscus RR, Robles BT, Waldman SA, Murad F (1987) Atrial natriuretic factors stimulate accumulation and efflux of cyclic GMP in C6-2B rat glioma and PC12 rat pheochromocytoma cell cultures. J Neurochem 48: 522-528.

Fiscus RR, Murad F (1988) cGMP-dependent protein kinase activation in intact tissues. Methods Enzymol 159: 150-159.

Fiscus RR, Zhou HL, Wang X, Han C, Ali S, Joyce CD, Murad F (1991) Calcitonin gene-related peptide (CGRP)-induced cyclic AMP, cyclic GMP and vasorelaxant responses in rat thoracic aorta are antagonized by blockers of endothelium-derived relaxant factor (EDRF). Neuropeptides 20: 133-143.

Peer-reviewed research articles since 2010:

75. Johlfs, M.G. and R.R. FISCUS. (2010) Protein kinase G type-I-alpha phosphorylates the apoptosis-regulating protein BAD at serine 155 and protects against apoptosis in N1E-115 cells. Neurochemistry International 56: 546-553.

76. Wong, J.C. and R.R. FISCUS. (2010) Protein kinase G activity prevents pathological-level nitric oxide-induced apoptosis and promotes DNA synthesis/cell proliferation in vascular smooth muscle cells. Cardiovascular Pathology 19: e221-e231. (Online Publishing)

77. Leung, E.L., Wong, J.C., Johlfs, M.G., Tsang, B.K., and R. R. FISCUS. (2010) Protein kinase G type I-alpha activity in human ovarian cancer cells significantly contributes to enhanced Src activation and DNA synthesis/cell proliferation. Molecular Cancer Research 8 (4): 578-591.

78. Leung, E.L, FISCUS, R.R., Tung, J.T., Tin, V.P., Cheng, L.C., Sihoe, A.D., Fink, L.M., Ma, Y. and M.P. Wong. (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE 5 (11): e14062. (Online Publishing)

79. FISCUS, R.R. and M.G. Johlfs. (2011) Protein kinase G type-1 phosphorylates c-Src at serine-17 and promotes cell survival, proliferation and attachment in human mesothelioma and non-small cell lung cancer cells. BMC Pharmacology 11 (Suppl. 1): 031. (Online Publishing)

80. Wong, J.C. and R.R. FISCUS. (2011) Essential roles of nitric oxide (NO)/cGMP/protein kinase G type-1-alpha (PKG-I-alpha) signaling pathway and atrial natriuretic peptide (ANP)/cGMP/PKG-I-alpha autocrine loop in promoting proliferation and cell survival of OP9 bone marrow stromal cells. Journal of Cellular Biochemistry 112: 829-839.

81. Wong, J.C., Bathina, M., and R.R. FISCUS. (2012) Cyclic GMP/protein kinase G type-Ia (PKG-I-alpha) signaling pathway promotes CREB phosphorylation and maintains higher c-IAP1, livin, survivin and Mcl-1 expression and the inhibition of PKG-I-alpha kinase activity synergizes with cisplatin in non-small cell lung cancer cells. Jouranl of Cellular Biochemistry 113: 3587-3598.

82. Urasaki, Y., Johlfs, M.G., FISCUS, R.R. and T.T. Le. (2012) Imaging immune and metabolic cells of visceral adipose tissues with multimodal nonlinear optical microscopy. PLoS ONE 7(6): e38418. (Online Publishing)

83. Rappa, G., Mercapide, J., Anzanello, F., Le, T.T., Johlfs, M.G., FISCUS, R.R., Wilsch-Brauninger, M, Corbeil, D. and Lorico, A. (2013) Wnt interaction and extracellular release of prominin-1 / CD133 in human malignant melanoma cells. Experimental Cell Research 319: 810-819.

84. Wong, J.C. and R.R. FISCUS. (2015) Resveratrol at anti-angiogenesis/anti-cancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs. AntiCancer Research 35: 273-282.

85. Johlfs, M.G., Gorjala, P., Urasaki, Y., Le, T.T. and R.R. FISCUS. (2015) Capillary isoelectric focusing immunoassay for fat cell differentiation proteomics. PLoS ONE 10(7):e0132105.

86. Urasaki, Y., FISCUS, R.R. and T.T. Le. (2016) Molecular classification of fatty liver by high-throughput profiling of protein post-translational modifications. Journal of Pathology ( J Pathol. 2016 Jan 4. doi: 10.1002/path.4685. [Epub ahead of print]; PMID: 26725750 . )

87. Wong, J.C., Vo, V., Gorjala, P. and R.R. FISCUS. (2017) Pancreatic beta-cell survival and proliferation are promoted by protein kinase G type-I-alpha and downstream regulation of Akt/ FoxO1. Diabetes & Vascular Disease Research 14(5): 434-449. DOI: 10.1177/1479164117713947.

88. Urasaki, Y., FISCUS, R.R. and T.T. Le. (2018) Detection of cell-cycle-regulated negative feedback phosphorylation of mitogen-activated protein kinases in breast carcinoma with nanofluidic proteomics. Scientific Reports-Nature.com 8:9991. DOI: 10.1038/s41598-018-28335-8.

Book chapters:

1. FISCUS, R.R., and S.K. Ming. (2000) Biology of ageing. Chapter 2. In: Medicine and Surgery in the Older Person, eds. W.S. Pang, M.K. Teoh and S.K. Ming, Armour Publishing Pte Ltd, Singapore, pp. 29-42.

2. FISCUS, R.R., Chan, G.H.H., and A.C.Y. Ma. (2001) Diabetes mellitus (DM) causes severe impairment of hypotensive responses in vivo and vasorelaxant responses in vitro to the neuropeptide CGRP. In: Peptides: The Wave of the Future, ed. M. Lebl and R.A. Houghten, Am. Peptide Soc, San Diego, California, USA, pp. 973-975.

3. Chan, G.H.H. and R.R. FISCUS. (2001) Age-related decreases of calcitonin gene-related peptide (CGRP)-induced hypotension in vivo and vasorelaxant responses in vitro in rats. In: Peptides: The Wave of the Future, ed. M. Lebl and R.A. Houghten, Am. Peptide Soc, San Diego, California, USA, pp. 746-748.

4. FISCUS, R.R. (2005) Molecular mechanisms of natriuretic peptide (ANP & BNP)/nitric oxide-induced protection against apoptosis in neural cells and synergistic enhancement of adrenomedullin/CGRP-induced vasodilation. In: Peptide Science 2004, ed. Y. Shimohigashi, The Japanese Peptide Society, Osaka, Japan, pp. 9-12.

5. FISCUS, R.R., Leung, E.L., Wong, J.C. and M.G. Johlfs (2012) Nitric oxide/protein kinase G-I-alpha promotes c-Src activation, proliferation and chemoresistance in ovarian cancer. Chapter 16 in “Ovarian Cancer – Basic Science Perspective”, ed. S. Farghaly, INTECH, pp. 315-334.

6. FISCUS, R.R. and M.G. Johlfs (2012) Protein kinase G (PKG): Involvement in promoting neural cell survival, proliferation, synaptogenesis and synaptic plasticity and the use of new ultrasensitive capillary-electrophoresis-based methodology for measuring PKG expression and molecular actions. Chapter 18 in “Protein Kinase Technologies”, ed. H. Mukai, in the series NEUROMETHODS, Vol. 18, Springer-Verlag, pp. 319-348.

7. Wong, J.C. and R.R.FISCUS. (2013) Protein kinase G-I-alpha hyperactivation and VASP phosphorylation in promoting ovarian cancer cell migration and platinum resistance. Chapter 12 in “Ovarian Cancer – A Clinical and Translational Update”, ed. I. Diaz-Padilla, INTECH, Section 4. Molecular Pathogenesis and Targeting Therapies, pp. 251-273.

8. Wong, J.C., Gorjala, P., Costantino, B. and R.R. FISCUS. (2016) Anti-angiogenic and anti-cancer effects by targeting the protein kinase G type-I-alpha (PKG-I-alpha) signaling pathway and its downstream effects on expression of inhibitor of apoptosis proteins, c-IAP1, Livin and Survivin. Chapter 10 in “Gynecologic Cancers – Basic Sciences, Clinical and Therapeutic Perspectives”, ed. S. Farghaly, INTECH, pp. 221-235.

Review Articles:

1. FISCUS, R.R. (1988) Molecular mechanisms of endothelium-mediated vasodilation. Seminars in Thrombosis and Hemostasis Suppl. 14: 12-22.

2. FISCUS, R.R., and W.H. Wehrmacher. (1988) Clinical trials of atrial natriuretic peptide in the treatment of congestive heart failure. Practical Cardiology 14 (11): 73-78.

3. FISCUS, R.R. (2002) Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival of neural cells. Neurosignals 11: 175-190.

4. Fung, E, FISCUS, R.R., Yim, A.P.C., and A.A. Arifi. (2005) The potential use of type-5 phosphodiesterase inhibitors in coronary artery bypass graft surgery. Chest 128: 3065-3073.

Presentations at Scientific Meetings:

Fiscus, R.R. (presenter), Johlfs, M.G., Morrill, S., Costantino, B., Gorjala, P., and J.C. Wong. (March 2017) Is Alzheimer’s disease actually “Type-3 Diabetes”? Molecular link involving insulin resistance and dysfunction of the brain’s nitric oxide (NO)-cGMP-PKG-I-alpha signaling pathway that normally protects neurons via increasing the cytoprotective phospho-proteins p-Akt, p-BAD and p-CREB. Podium Presentation, 3rd Annual Roseman Research Symposium at Henderson, NV campus of Roseman University of Health Sciences.

Morrill, S. (presenter), Johlfs, M.G., Costantino, B. and R.R. Fiscus. (March 2017) Molecular link between Alzheimer's disease and diabetes: Kinase activity of PKG-I-alpha, meditor of physiological-level nitric oxide (NO)-induced neuroprotection, suppresses amyloid precursor protein (APP)/A-beta expression in NG108-15 cholinergic neuronal cells and this kinase activity is damaged by high glucose levels. Poster presentation at the 3rd Annual Roseman Research Symposium at the Henderson, NV campus of Roseman University of Health Sciences.

Fiscus, R.R. (presenter), Johlfs, M.G., Wong, J.C., Gorjala, P. and V. Vo. (December 2017) Discovery of novel diabetes-damaged proteins ( e.g. PKG-I-alpha that normally promotes pancreatic beta-cell survival / regeneration and angiogenesis / endothelial cell survival and protects against obesity / fat cell differentiation and inflammation ) by using a new ultrasensitive robotic capillary isoelectric focusing (cIEF) technology. Poster presentation at the 15th Annual World Congress of Insulin Resistance, Diabetes & Cardiovascular Disease, Los Angeles, CA.

Fiscus, R.R. (presenter), Vo, V. and M.G. Johlfs. (January 2018) 1.1B4 cells, newly-developed human pancreatic beta-cell line, as model for discovery of novel proteins promoting human beta-cell survival: Co-localization of two pro-survival proteins, c-Src and PKG-I-alpha, at insulin secretory granules and the nucleus. Selected by scientific committee for presentation at the 2018 City of Hope –Rachmiel Levine-Arthur Riggs Diabetes Research Symposium, Pasadena, CA, Jan. 31 – Feb. 3, 2018.