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Randy Strich, Ph.D.

Professor

Science Center 354
856-566-6043
strichra@rowan.edu

Education

University of Illinois at Urbana, IL 
Ph.D. (Microbiology), 1986

University of Illinois at Urbana, IL 
M.S. (Microbiology), 1983

University of Pennsylvania, PA 
B.A. (Biology), 1980

Research Interests

Historically, research on the stress response has focused on how damage recognition/signal transduction systems modify transcription factor activity to remodel gene expression programs. However, it has become increasing clear that cytoplasmic organelles are both receptors of, and signaling platforms for, the stress response. Concurrent with changes in nuclear gene expression, cellular damage induces extensive mitochondrial fragmentation and mitochondrial outer membrane permeability (MOMP) that initiates the intrinsic regulated cell death (RCD, a.k.a. apoptosis) pathway. Therefore, the cell must coordinate both the nuclear and mitochondrial stress responses to make the correct decision between arresting cell division and repairing the damage or initiating cell death. We found that the conserved cyclin C protein directly connects both the nuclear and mitochondrial stress responses mediating the decision of whether to initiate RCD (reviewed in Ref 13). This role is conserved from yeast to man and provides the foundation for two ongoing projects in my laboratory.

Cyclin C suppresses pancreatic tumor formation. Under normal conditions, cyclin C binds and activates its cyclin-dependent protein kinase Cdk8 to activate or repress the transcription of genes that respond to extracellular signals or cell damage (Refs 4,5). However, we found that cyclin C exits the nucleus (without Cdk8) in response to stress (Refs 9,11). In the cytoplasm, cyclin C binds and activates the mitochondrial fission protein Drp1 (Ref 1). Knockout mouse embryonic fibroblast (MEF) studies indicate that cyclin C is both necessary and sufficient to induce the extensive mitochondrial fragmentation observed in stressed cells (Ref 11).  Finally, we found that cyclin C is also required for cell death pathway initiation (Ref 2). These results prompted our studies to determine if cyclin C suppresses tumor formation. This was indeed the case in two murine cancer models, thyroid (Ref 3) and pancreas (Ref 8). Importantly, the pancreatic studies revealed that cyclin C suppressed both the more common adenocarcinoma as well as the rarer neuroendocrine tumor. We are currently studying the role cyclin C plays in both diseases using both animal and cell culture models.  

Mitochondrial dysfunction in the MED13L syndrome disorder. Spectrum disorders are among the most difficult diseases to diagnose and treat as patients do not present with all symptoms and their severity can vary from mild to severe. The second direction in my laboratory focuses on a developmental disorder called MED13L syndrome. MED13L syndrome is an autosomal dominant spectrum disorder identified in children as a group of clinically variable symptoms including heart malformation, intellectual disabilities, and hypotonia. Unbiased DNA sequence analysis of randomly selected patients displaying intellectual disabilities found de novo MED13L mutations in ~ 3% of all cases examined. These findings suggest that MED13L is an important protector of normal development. MED13L is the anchor protein that tethers cyclin C in the nucleus (Ref 10). We found aberrant cyclin C cytoplasmic localization in a cell line derived from a MED13L syndrome individual (Ref 6). Mis-localization of cyclin C resulted in continuously fragmented mitochondria and organelle dysfunction. Currently, my laboratory utilizes murine cell culture and patient derived cell lines to determine how general a phenomenon mitochondrial dysfunction is in MED13L syndrome and whether this phenotype can be reversed.

 

Selected Publications (last five years):

 1) Ganesan, V., Willis, S.D., Chang, K.T., Beluch, S., Cooper, K.F., and Strich, R. (2019). Cyclin C directly stimulates Drp1 GTP affinity to mediate stress-induced mitochondrial hyperfission. Mol Biol Cell 30, 302-311. 10.1091/mbc.E18-07-0463. https://www.ncbi.nlm.nih.gov/pubmed/30516433

2) Jezek, J., Chang, K.T., Joshi, A.M., and Strich, R. (2019). Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment. EMBO Rep 20, e47425. 10.15252/embr.201847425. http://www.ncbi.nlm.nih.gov/pubmed/31385392

3) Jezek, J., Wang, K., Yan, R., Di Cristofano, A., Cooper, K.F., and Strich, R. (2019). Synergistic repression of thyroid hyperplasia by cyclin C and Pten. J Cell Sci 132. 10.1242/jcs.230029.  https://www.ncbi.nlm.nih.gov/pubmed/31331961

4) Stieg, D.C., Chang, K.T., Cooper, K.F., and Strich, R. (2019). Cyclin C Regulated Oxidative Stress Responsive Transcriptome in Mus musculus Embryonic Fibroblasts. G3 (Bethesda) 9, 1901-1908. 10.1534/g3.119.400077. https://www.ncbi.nlm.nih.gov/pubmed/31036676

5) Stieg, D.C., Cooper, K.F., and Strich, R. (2020). The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription. J Biol Chem 295, 16280-16291. 10.1074/jbc.RA120.015215. https://www.ncbi.nlm.nih.gov/pubmed/32934007

6) Chang, K.T., Jezek, J., Campbell, A.N., Stieg, D.C., Kiss, Z.A., Kemper, K., Jiang, P., Lee, H.O., Kruger, W.D., van Hasselt, P.M., and Strich, R. (2022). Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts. iScience 25, 103823. 10.1016/j.isci.2022.103823. https://www.ncbi.nlm.nih.gov/pubmed/35198885

7) Jiang, P., Kemper, K.M., Chang, K.-T., Qiang, C., Li, Y., Guan, L., van Hasselt, P.M., Caradonna, S.J., and Strich, R. (2022). An in situ cut-and-paste genome editing platform mediated by CRISPR/Cas9 or Cas12a. BioVix bioRxiv 2022.03.30.486486; doi.org/10.1101/2022.03.30.486486 .

8) Campbell, K.S., Cai, K.Q., Hanley, S., Stieg, D.C., and Strich, R. (2022). Ccnc suppresses pancreatic ductal adenocarcinoma and neural endocrine progression in murine Kras model. Oncogenesis.  Submitted.

 

Older important papers:

 9) Cooper, K.F., Khakhina, S., Kim, S.K., and Strich, R. (2014). Stress-induced nuclear-to-cytoplasmic translocation of cyclin C promotes mitochondrial fission in yeast. Dev Cell 28, 161-173. 10.1016/j.devcel.2013.12.009. http://www.ncbi.nlm.nih.gov/pubmed/24439911

10) Khakhina, S., Cooper, K.F., and Strich, R. (2014). Med13p prevents mitochondrial fission and programmed cell death in yeast through nuclear retention of cyclin C. Mol Biol Cell 25, 2807-2816. 10.1091/mbc.E14-05-0953. http://www.ncbi.nlm.nih.gov/pubmed/25057017

11) Wang, K., Yan, R., Cooper, K.F., and Strich, R. (2015). Cyclin C mediates stress-induced mitochondrial fission and apoptosis. Mol Biol Cell 26, 1030-1043. 10.1091/mbc.E14-08-1315. http://www.ncbi.nlm.nih.gov/pubmed/25609094

 

Reviews:

 12) Jezek, J., Cooper, K.F., and Strich, R. (2018). Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression. Antioxidants (Basel) 7. 10.3390/antiox7010013. https://www.ncbi.nlm.nih.gov/pubmed/29337889

13) Jezek, J., Smethurst, D.G.J., Stieg, D.C., Kiss, Z.A.C., Hanley, S.E., Ganesan, V., Chang, K.T., Cooper, K.F., and Strich, R. (2019). Cyclin C: The Story of a Non-Cycling Cyclin. Biology (Basel) 8. 10.3390/biology8010003. https://www.ncbi.nlm.nih.gov/pubmed/30621145

14) Jezek, J., Cooper, K.F., and Strich, R. (2021). The Impact of Mitochondrial Fission-Stimulated ROS Production on Pro-Apoptotic Chemotherapy. Biology (Basel) 10. 10.3390/biology10010033. https://www.ncbi.nlm.nih.gov/pubmed/33418995