Faculty & Staff at TUC

Daniel  Keppler, PhD

Daniel Keppler

College: College of Pharmacy (COP)

Department: Biological & Pharmaceutical Sciences

Title: Associate Professor and Director of the MS Graduate Program

Phone: (707) 638-5956

Fax: (707) 638-5959

E-Mail: daniel.keppler@tu.edu

Office: Administration & Faculty 2, Rm. 111

Institution Degree Field of Study Obtained
University Paris-6, France B.Sc. (Maitrise) Marine Biology 1982
University Paris-6, France M.Sc. (D.E.A.) Biochemistry 1983
University Paris-6, France Ph.D. Biochemistry 1988

1. COP Program

P1 Fall Semester 
PHRM 601: Biological Sciences 1 (Participating Faculty Member) 
Topics:

  • Cell Signaling: Receptors & Signal Transduction
  • Cell Pathology: Stress Responses, Injury & Cell Death 

P1 Spring Semester 
PHRM 605: Biological Sciences 2 (Participating Faculty Member) 
Topics:

  • Immune-Mediated Diseases of the Gastro-Intestinal Tract

P2 Fall Semester 
PHRM 609: Biological Sciences 3 (Participating Faculty Member) 
Topics:

  • Cerebrovascular System & Ischemic Stroke
  • Hemorrhagic Stroke, Traumatic Brain Injury & Seizure Disorders
  • Pathophysiology of Movement Disorders (ALS, PD & HD)
  • Inherited Metabolic Diseases (Lysosomal Storage Diseases)
  • Pathophysiology of the Pituitary Gland
  • Pathophysiology of the Adrenal Cortex 

P2 Spring Semester 
PHRM 613: Biological Sciences 4 (Course Director) 
Topics:

  • Cancer Biology-1: Genetic & Cellular Basis of Neoplasia
  • Cancer Biology-2: Tumor Viruses (HPV), Oncogenes & Tumor Suppressor Genes
  • Cancer Biology-3: Receptor Tyrosine Kinases (EGFR) & Mitogenic Signaling
  • Cancer Biology-4: Tumor Invasion (EMT) & Metastasis
  • Cancer Biology-5: Tumor Angiogenesis & VEGFR Signaling
  • Cancer Biology-6: DNA Damage Responses & Cellular Senescence

2. MS-MHS-COP Program

Fall Semester
HS 604-P: Journal Club (Course Coordinator) 

Spring Semester 
HS 609-P: Journal Club (Course Coordinator) 

3. Implementation of ExamSoft in the College of Pharmacy

Fall 2013-Present: Co-Administrator and Faculty Liaison

  • Created categories for the query of the question bank
  • Provided group and individual training to the faculty
  • Mentored individual faculty members
  • Acted as liaison between the staff and the faculty
  • Coordinated tasks before, during and after exams

Last updated: Nov. 7, 2014

Role of Cystatins in Aging and Cancer 

Our laboratory is interested in the role of endogenous protease inhibitors in normal cellular homeostasis and in proliferative diseases such as neoplasia. We are particularly keen in understanding the role of the cysteine protease inhibitors known as cystatins (CSTs) in cell proliferation, differentiation and senescence. There are a dozen distinct cystatins in mammals. In the test tube, these cystatins behave like potent inhibitors of lysosomal cysteine proteases such as the cathepsins B, H, K, L and S. Due to the reversible nature of the interaction of cystatins with cathepsins it has been difficult to demonstrate the formation of enzyme-inhibitor complexes in situ. Moreover, cystatins – particularly secreted cystatins - seem to have acquired additional functions in cell and tissue homeostasis. Indeed, cystatins have been implicated in many important biological processes, such as cell survival, proliferation, migration, differentiation, senescence and modulation of immune function. Therefore, an important challenge of the research in this field is to determine their precise enzyme targets. The short-term goal of our endeavors is to define to what extent inhibition of peri- or intracellular proteases is responsible for the cystatin's multiple biological functions. Thelong-term goal is to move this research into the clinical arena where cystatin-derived reagents can be tested for their efficacy as novel diagnostic/prognostic tools or therapeutic agents. 

Currently, we are pursuing three projects

1. Role of CST1 as a novel gene induced during cellular senescence. Expression, secretion, localization and role on neighboring cells and tissues. Role of CST1 (and the gene product Cst-1/cystatin SN) as a novel biomarker of cellular senescence.

2. Role of CST6 as a novel tumor suppressor gene. Expression, secretion, localization and role during early tumor formation and progression.

3. Role of CST3 in cell survival and proliferation. Identification and characterization of a potential cell surface cystatin-binding/receptor molecule

Research on cystatins provides an excellent environment for the motivation and training of young scientists. This research has also great potential for translational applications and drug development. Indeed, cystatins have been implicated in embryonic stem cell proliferation and differentiation as well as in progression of age-associated diseases such as neurodegenerative, cardiovascular and malignant diseases.

Last updated: Dec. 4, 2013

Grants:

Virtual Discovery Grant (Principal Investigator: Daniel Keppler), Karmanos Cancer Institute, Detroit, Michigan. 

Institutional Research Grant 85-003-14 (PI: Fred R. Miller; Project PI: Daniel Keppler), American Cancer Society, Wayne State University School of Medicine, Detroit, Michigan. 

Research Grant 5-R21 CA91785 (PI: Daniel Keppler), National Institutes of Health/National Cancer Institute. 

Start-up Funds from Louisiana State University-Health Sciences Center and Feist-Weiller Cancer Center, Shreveport, Louisiana. 

Young Investigator Award (PI: Daniel Keppler), The Edward P. Stiles Trust Fund and The Biomedical Research Foundation of Northwest Louisiana, Shreveport, Louisiana. 

Institutional Research Funds (PIs: Daniel Keppler & Athena W. Lin), Touro University-California, Vallejo, California 

Contracts:

Keppler, D. Invited Editor, volume on Cervical Cancer. Methods in Molecular Biology Series (Walker JM, Ed.). Springer Protocols (Marton, PJ, Senior Ed.). Springer Publishing Group/Humana Press, New York, USA. 2011–2013. URL.

Keppler, D. Founding Editor of the open access journal Cellular Senescence and Therapy. DeGruyter-Versita Open Access Publishers, London, Warsaw. 2013-2015.

Last updated: Nov. 7, 2014

Original Observations in Refereed Journals (Selected): 

Keppler, D., Dalet-Fumeron, V., Pagano, M. and Engler, R. (1988). Purification and characterisation of two different precursor forms of the cathepsin B-like proteinase from malignant ascitic fluid. Biol. Chem. 369: Suppl.,185-190. Go to: PubMed

Keppler, D., Fondanèche, M. C., Dalet-Fumeron, V., Pagano, M. and Burtin, P. (1988). Immunohistochemical and biochemical study of a cathepsin B-like proteinase in human colonic cancers. Cancer Res. 48: 6855-6862. Go to:PubMed

Keppler, D., Markert, M., Carnal, B., Berdoz, J., Bamat, J. and Sordat, B. (1996). Human colon carcinoma cells synthesize and secrete alpha-1-proteinase inhibitor. Biol. Chem. 377: 301-311. Go to: PubMed

Keppler, D., Sameni, M., Moin, K., Mikkelsen, T., Diglio, C.A. and Sloane, B.F. (1996). Tumor progression and angiogenesis: cathepsin B & Co. Biochem. Cell Biol. 74: 799-810. Go to: PubMed

Linebaugh, B.E., Sameni, M., Day, N.A., Sloane, B.F. and Keppler, D. (1999). Exocytosis of active cathepsin B: enzyme activity at pH 7.0, inhibition and molecular mass. Eur. J. Biochem. 264: 100-109. Go to: PubMed

Waghray, A., Keppler, D., Sloane, B.F., Schuger, L. and Chen, Y.Q. (2002). Analysis of a truncated form of cathepsin H in human prostate tumor cells. J. Biol. Chem. 277: 11533-11538. Go to: PubMed

Shridhar, R., Zhang, J., Song, J., Booth, B.A., Kevil, C.G., Sotiropoulou, G., Sloane, B.F. and Keppler, D. (2004). Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells. Oncogene 23: 2206-2215 (Dec. 15, 2003, E-pub ahead of print). Go to: PubMed

Zhang, J., Shridhar, R., Dai, Q., Song, J., Barlow, S.C., Yin, L., Sloane, B.F., Miller, F.R., Meschonat, C., Li, B.D.L., Abreo, F. and Keppler, D. (2004). Cystatin M: A novel candidate tumor suppressor gene for breast cancer. Cancer Res. 64: 6957-6964. Go to: PubMed

Song, J., Jie, C., Polk, P., Shridhar, R., Clair, T., Zhang, J., Yin, L., and Keppler, D. (2006). The candidate tumor suppressor CST6 alters the gene expression profile of human MDA-MB-435S cells: Down-regulation of the potent mitogenic, motogenic and angiogenic factor autotaxin. Biochem. Biophys. Res. Commun. 340: 175-182 (Dec. 9, 2005, E-pub ahead of print). Go to: PubMed

Mason, D.X., Keppler, D., Zhang, J., Jackson, T., Seger, Y.R., Matsui, S.I., Abreo, F., Cowell, J.K., Hannon, G.J., Lowe, S.W. and Lin, A.W. (2006). Defined genetic events associated with the spontaneous in vitro transformation of E1A/Ras-expressing human IMR90 fibroblasts. Carconigenesis 27: 350-359 (Nov. 9, 2005, E-pub ahead of print).DK is a co-1st author. Go to: PubMed

Lü, J., Qian, J., Keppler, D. and Cardoso, W.V. (2007). Cathepsin H is an FGF10 target involved in the regulation of BMP4 signaling during mouse lung branching morphogenesis. J. Biol. Chem. In press (May 11, 2007, E-pub ahead of print). Go to: PubMed

Rivenbark, A.G., Livasy, C.A., Boyd, C.E., Keppler, D. and Coleman, W.B. (2007). Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions. Exp. Mol. Pathol. In press (April 18, 2007, E-pub ahead of print). Go to: PubMed

Veena, M.S., Lee, G., Keppler, D., Mendonca, M.S., Redpath, J.L., Stanbridge, E.J., Wilczynski, S.P., and Srivatsan, E.S. (2008). Inactivation of the cystatin E/M (CST6) tumor suppressor gene in cervical cancer. Genes Chr. Cancer. 47: 740-754. Go to: PubMed

Keppler, D. (2009). Structured review on CST6 (11q13). Atlas Genet. Cytogenet. Oncol. Haematol. Go to: URL 

Keppler, D., Zhang, J., Bihani, T. and Lin, A.W. (2011). Novel expression of CST1 as candidate senescence marker.  Journal of Gerontology A: Biological Sciences & Medical Sciences. 66A(7):723-31. PubMed.

Invited Reviews and Essays (Selected): 

Keppler, D., Abrahamson, M. and Sordat, B. (1994). Secretion of cathepsin B and tumour invasion. Biochem. Soc. Trans. 22: 43-49. Go to: PubMed 

Keppler, D. and Sierra, F. (2005). Role of cystatins in tumor neovascularization. Future Oncology. 1: 661-672. Go to:PubMed

Keppler, D. (2006). Towards novel anti-cancer strategies based on cystatin function. Cancer Lett. 235: 159-176 (May 10, 2006, E-pub ahead of print). Go to: PubMed

Nunez, L.M., and Keppler, D. (2009). Cystatins. In: Encyclopedia of Cancer (Schwab, M., Ed.). Part 3, pp. 801-805. Springer Verlag, Heidelberg. Go to: URL 

Books & Book Chapters: 

Keppler, D. and Sloane, B.F. (1996). Cathepsin B: multiple enzyme forms from a single gene and their relation to cancer. In: Enzyme & Protein. Proteolytic Enzymes in Cancer Invasion (Ossowski, L. and Mira y Lopez, R., Eds.). Vol. 49. S. Karger AG, Basel, pp. 94-105. 

Shridhar, R., Sloane, B.F. and Keppler, D. (2000). Inhibitors of Papain-like Cysteine Peptidases in Cancer. In: Retinoids; Proteases as Targets for Therapy. K. von der Helm, B.D. Korant and J.C. Cheronis, Eds. Handbook of Experimental Pharmacology, Vol. 140, pp. 301-328, Springer Verlag, Berlin Heidelberg.

Keppler, D. and Lin, A.W. (Eds.) (2015). Cervical Cancer: Methods & Protocols. In: Methods in Molecular Biology (Walker, J.M., Series Ed.), Vol. 1249. Springer Science+Business Media/Humana Press, New York.

Diep, C.M, Kaur, G., Keppler, D. and Lin, A.W. (2015). Retroviral expression of human cystatin genes in HeLa cells. Methods in Molecular Biology 1249: 121-131.

Last updated: Nov. 7, 2014

May 1988, PhD in Biochemistry, Summa Cum Laude 

1986-1988, Graduate Research Assistantship from ARC (Association pour la Recherche sur les Cancers). 

1988-1989, Fellowship for Innovative Research from ANVAR (Agence Nationale pour la Valorisation de la Recherche). 

2000, Basic Research Project Evaluation for the Arkansas Science & Technology Authority (ASTA), Little Rock, Arkansas. 

Sep. 2000, Recipient of an Insight Award to Stamp Out Breast Cancer from the National Institutes of Health/National Cancer Institute. 

Jan. 2001, Recipient of a Young Investigator Award from The Edward P. Stiles Trust Fund at LSU-HSC in Shreveport and from The Biomedical Research Foundation of Northwest Louisiana. 

2004, Ad hoc Member and Primary Reviewer of NIH/NIDCR/DSR, Special Grants Review Committee, National Institute of Dental & Craniofacial Research, National Institues of Health, Bethesda, Maryland, USA. 

2004-2007, Ad hoc Member of the Institutional Research Advisory Committee at LSU-HSC in Shreveport, Louisiana.

2010-2012, Ad hoc Member of the Institutional Research Award Program (IRAP) Review Committee for the College of Education and Health Sciences at Touro University California.

Employer Title From - To
IRSC-CNRS, Villejuif-Paris, France Research Associate 1988-1989
ISREC, Epalinges/Lausanne, Switzerland Postdoctoral Fellow 1990-1995
Wayne State Univ. School of Med., Detroit, MI Research Assist. Prof. in Pharmacology 1995-2000
Louisiana State Univ.-HSC in Shreveport, LA Assist. Prof. in Cell. Biol. & Anatomy 2001-2007
Touro Univ. California, Vallejo, CA Assoc. Prof. in Biol. Sci., Pharmacy 2007-present
Last Updated: 5/5/17