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Scott C. Schuyler

 

Scott C. Schuyler

Appointments：Associate professor

Lab：Yeast biochemistry& genetics lab

Education：Ph.D.

School/Nation：Harvard University/USA

Tel: (03)211-8800 ext:3596

E-mail: schuyler@mail.cgu.edu.tw

Research website: https://scs03596.wixsite.com/scslab

研究室現有： 博士後研究員  人

博士班研究生    人

碩士班研究生  人

專任研究助理  4 人

大學部專題生    人

Mitotic Spindle Checkpoint

The mitotic spindle checkpoint prevents chromosome loss.  I want to understand how this checkpoint regulates chromosome segregation during eukaryotic cell division, primarily by studying how the spindle checkpoint inhibits the cell cycle regulator the Anaphase-Promoting Complex (APC).  Yeast genetics, cell biology, and biochemistry in combination are powerful tools for exploring the molecular roles of protein complexes.  In the lab, I use my training in these fields to develop biochemical, cell biological and genetic approaches to ask how the mitotic spindle checkpoint functions to inhibit APC.

 

 

 

 

 

 

 

 

 

 

One of the most successful chemotherapeutic agents has been mitotic poisons, such as microtubule poisons like paclitaxel.  Although the exact cellular mechanisms leading to cancer cell death are unclear, mitotic poisons are thought to act by creating a delay in mitosis, which in turn leads to cells undergoing apoptosis. 

Cancer cells may not respond to mitotic poison-based treatments in the clinic, or may develop resistance to the therapy.  Although the cellular mechanisms explaining mitotic poison resistance in each cancer type and each cancer patient remains unclear, ultimately the mitotic poison resistance allows the cancer cells to escape the delay in cell cycle progression in mitosis and under go ‘mitotic slippage’, and re-enter the cell cycle rather than undergoing apoptotic cell death. 

Figure 1. Cancer cell survival requires the APC/CCdc20 enzyme for ‘mitotic slippage’ and continued cell division to avoid apoptotic cell death.  Currently, there are no known APC/CCdc20 enzyme drug inhibitors.

‘Mitotic slippage’ requires the activity of the master cell cycle regulator, an E3-Ubiquitin Ligase, called the Anaphase-Promoting Complex/Cyclosome (APC/C), and the essential mitotic co-factor Cdc20 (Cell Division Cycle 20) (Huang, et al., 2010a; Schuyler, et al., 2012).

This knowledge has led to a recent set of studies to investigate how to prevent ‘mitotic slippage’, and thus promote cancer cell apoptosis.

In the lab, we have employed the simple eukaryote budding yeast to discover novel and unique peptides inhibitors that can target the APC/C enzyme activity.  We have also demonstrated that our peptide inhibitors makes cells specifically sensitive to an anti-mitotic microtubule poison in vivo when over-expressed in the cell.

Our long-term goal is the creation of a new class of anti-cancer agents specifically targeting APC/CCdc20 activity that can be used in combination with anti-mitotic drug cancer therapies. We expect two primary benefits:

1.  A new peptide inhibitor against APC/CCdc20 activity will be developed and characterized.

2.  The initial characterization using human colon cancer cells of a potentially novel combinatorial therapeutic agent will have been completed.

Publications:

  1. Schuyler SC# and Chen HY. (2021) Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons. Int. J. Mol. Sci. 22, 7985. #corresponding author
  2. Swamy KBS, Schuyler SC and Leu JY.  (2021) Protein Complexes Form a Basis for Complex Hybrid Incompatibility.  Front Genet. Feb 9; 12:609766.
  3. Schuyler SC#, Wang L-I*, Ding Y-S*, Lee Y-C and Chen H-Y. (2020) Deletion of Budding Yeast MAD2 Suppresses Clone-to-Clone Differences in Artificial Linear Chromosome Copy Numbers and Gives Rise to Higher Retention Rates. Microorganisms. Sept 29; 8(10), 1495. *equal contribution #corresponding author
  4. Alson D, Schuyler SC, Yan BX, Samimuthu K, Qiu JT. (2020) Combination Vaccination with Tetanus Toxoid and Enhanced Tumor-Cell Based Vaccine Against Cervical Cancer in a Mouse Model. Front Immunol. May 27;11:927.
  5. Yang SC, Liu JJ, Wang CK, Lin YT, Tsai SY, Chen WJ, Huang WK, Tu PA, Lin YC, Chang CF, Cheng CL, Lin H, Lai CY, Lin CY, Lee YH, Chiu YC, Hsu CC, Hsu SC, Hsiao M, Schuyler SC, Lu FL, Lu J.  (2019) Down-regulation of ATF1 leads to early neuroectoderm differentiation of human embryonic stem cells by increasing the expression level of SOX2.  FASEB J. Sep;33(9):10577-10592.
  6. Qiu JT*#, Alson D*, Lee T-H, Tsai C-C, Yu T-W, Chen Y-S, Cheng Y-F, Lin C-C, Schuyler SC#. (2019) Effect of Multiple Vaccinations with Tumor Cell-Based Vaccine with Codon-Modified GM-CSF on Tumor Growth in a Mouse Model.  Cancers. Mar 15;11(3).  *equal contribution #co-corresponding authors
  7. Schuyler SC*#, Wu YFO*, Chen HY*, Ding YS, Lin CJ, Chu YT, Chen TC, Liao L, Tsai WW, Huang A, Wang LI, Liao TW, Jhuo JH and Cheng V.  (2018) Peptide inhibitors of the anaphase promoting-complex that cause sensitivity to microtubule poison.  PLOS ONE, Jun 8;13(6):e0198930. *equal contribution #corresponding author

 

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