Mornings with art, lessons learned: Feedback regulation, restriction threshold biology, and redundancy govern molecular stress responses

Work from the laboratory of Dr. Arthur B. Pardee has highlighted basic principles that govern cellular and molecular biological processes in living cells. Among the most important governing principles in cellular and molecular responses are: (i) threshold “restriction” responses, wherein a level of...

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Published in:Journal of cellular physiology 2006-12, Vol.209 (3), p.604-610
Main Authors: Bey, Erik A., Wuerzberger-Davis, Shelly M., Pink, John J., Yang, Chin-Rang, Araki, Shinako, Reinicke, Kathryn E., Bentle, Melissa S., Dong, Ying, Cataldo, Eva, Criswell, Tracy L., Wagner, Mark W., Li, Longshan, Gao, Jinming, Boothman, David A.
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Cell Cycle - drug effects
Cell Cycle - physiology
Cell Death - drug effects
Cell Physiological Phenomena
Clusterin - genetics
Clusterin - metabolism
DNA Mismatch Repair
Feedback, Physiological - physiology
Humans
Naphthoquinones - pharmacology
Naphthoquinones - therapeutic use
Neoplasms - drug therapy
Radiation-Sensitizing Agents - pharmacology
Radiation-Sensitizing Agents - therapeutic use
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Summary:Work from the laboratory of Dr. Arthur B. Pardee has highlighted basic principles that govern cellular and molecular biological processes in living cells. Among the most important governing principles in cellular and molecular responses are: (i) threshold “restriction” responses, wherein a level of response is reached and a “point of no return” is achieved; (ii) feedback regulation; and (iii) redundancy. Lessons learned from the molecular biology of cellular stress responses in mammalian cancer versus normal cells after ionizing radiation (IR) or chemotherapeutic agent exposures reveal similar instances of these guiding principles in mammalian cells. Among these are the: (i) induction of cell death responses by β‐lapachone (β‐lap), a naphthoquinone anti‐tumor agent that kills cancer cells via an NQO1 (i.e., X‐ray‐inducible protein‐3, xip3)‐dependent mechanism; (ii) induction of secretory clusterin (sCLU) in response to TGF‐β1 exposure, and the ability of induced sCLU protein to down‐regulate TGF‐β1 signaling; and (iii) induction of DNA mismatch repair‐dependent G2 cell cycle checkpoint responses after exposure to alkylating agents. We have learned these lessons and now adopted strategies to exploit them for improved therapy. These examples will be discussed and compared to the pioneering findings of researchers in the Pardee laboratory over the years. J. Cell. Physiol. 209: 604–610, 2006. © 2006 Wiley‐Liss, Inc.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.20783