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 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 beta-lapachone (beta-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-beta1 exposure, and the ability of induced sCLU protein to down-regulate TGF-beta1 signaling; and (iii) induction of DNA mismatch repair-dependent G(2) 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.
Bey
Erik A
EA
Laboratory of Molecular Stress Responses, Department of Pharmacology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Wuerzberger-Davis
Shelly M
SM
Pink
John J
JJ
Yang
Chin-Rang
CR
Araki
Shinako
S
Reinicke
Kathryn E
KE
Bentle
Melissa S
MS
Dong
Ying
Y
Cataldo
Eva
E
Criswell
Tracy L
TL
Wagner
Mark W
MW
Li
Longshan
L
Gao
Jinming
J
Boothman
David A
DA
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002468:Cell Physiological Phenomena; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use
D051152:Clusterin; D009285:Naphthoquinones; D011838:Radiation-Sensitizing Agents; C014638:beta-lapachone