Project Grant R35GM152255

CELL CYCLE AND CHECKPOINT VARIATIONS IN DEVELOPMENT AND DISEASE - PROJECT SUMMARY THE CALVI LAB INVESTIGATES THE REGULATION OF CELL CYCLE AND GENOME INTEGRITY USING DROSOPHILA MELANOGASTER AS A MODEL SYSTEM. OUR ONGOING STUDIES ARE DEFINING THE VARIATIONS IN CELL CYCLE AND CHECKPOINTS IN DEVELOPMENT AND HOW THESE VARIATIONS ARE RELATED TO DISEASE. ONE CELL CYCLE VARIANT THAT WE HAVE FOCUSED ON IS CALLED THE ENDOCYCLE, WHICH IS A G / S CYCLE WITHOUT DIVISION THAT RESULTS IN LARGE, POLYPLOID CELLS. THE ENDOCYCLE IS A NORMAL VARIANT GROWTH PROGRAM IN A VARIETY OF TISSUES AND ORGANISMS INCLUDING HUMANS. IN RECENT YEARS, IT HAS BECOME INCREASINGLY CLEAR THAT MITOTICALLY DIVIDING CELLS CAN ALSO SWITCH TO POLYPLOID ENDOCYCLES IN RESPONSE TO CONDITIONAL INPUTS. WE CALL THESE INDUCED ENDOCYCLING CELLS (IECS) TO DISTINGUISH THEM FROM THE DEVELOPMENTAL ENDOCYCLING CELLS (DEVECS) THAT CONTRIBUTE TO THE GROWTH OF SPECIFIC TISSUES DURING DEVELOPMENT. WHILE IECS CAN BE BENEFICIAL FOR TISSUE REGENERATION, THEY ALSO CAN CONTRIBUTE TO TISSUE MALFORMATIONS AND CANCER. WE HAD PREVIOUSLY SHOWN THAT BOTH DEVECS AND IECS REPRESS THE P53 APOPTOTIC RESPONSE TO DNA DAMAGE, AND THAT IECS IN BOTH DROSOPHILA AND HUMAN CELL CULTURE CAN RETURN TO AN ERROR PRONE MITOSIS THAT COMPROMISES GENOME INTEGRITY. OUR EVIDENCE, TOGETHER WITH THAT FROM OTHER LABS AND THE CLINIC, HAS LED TO A PREVAILING MODEL THAT THE SURVIVAL AND DIVISION OF CANCER IECS CONTRIBUTES TO CANCER THERAPY RESISTANCE AND RELAPSE. NEVERTHELESS, MUCH REMAINS UNKNOWN ABOUT THE MECHANISMS THAT REGULATE IEC CYCLING, GROWTH, AND CHECKPOINT RESPONSES AND WHAT GLOBAL IMPACT THESE PROPERTIES HAVE ON TISSUE MALFORMATIONS AND TUMORIGENESIS. WE ARE CONTINUING TO ADDRESS THESE QUESTIONS USING DROSOPHILA AS A MODEL SYSTEM TO STUDY IECS IN VIVO. THIS HAS LED TO A FUNDAMENTALLY NEW VIEWPOINT THAT IECS ARE NOT JUST A SWITCH IN CELL CYCLE, BUT ALSO REPRESENT A DISTINCT CELL STATE WITH MODIFIED GROWTH, STRESS RESPONSE, AND SIGNALING PATHWAYS THAT HAVE BOTH CELL AUTONOMOUS AND NONAUTONOMOUS EFFECTS ON TISSUE GROWTH. WE ARE USING INTEGRATED CELL, MOLECULAR AND GENOMIC APPROACH TO FURTHER DEFINE THIS CELL STATE AND UNCOVER NEW MECHANISMS BY WHICH IT AFFECTS TISSUE GROWTH AND ONCOGENESIS. AS PART OF THIS INQUIRY, WE CONTINUE TO DEFINE HOW PROAPOPTOTIC P53 TARGET GENES ARE REPRESSED IN ENDOCYCLING CELLS TO DISCOVER CONSERVED MECHANISMS THAT COUPLE APOPTOTIC COMPETENCE TO CELL CYCLE PROGRAMS. THESE ONGOING STUDIES INTO THE P53 PATHWAY HAVE LED US TO DISCOVER THAT DIFFERENT DROSOPHILA P53 PROTEIN ISOFORMS HAVE OVERLAPPING AND DISTINCT FUNCTIONS IN MULTIPLE CELL TYPES AND PROCESSES. WE ARE INVESTIGATING HOW THESE P53 FUNCTIONS ARE REGULATED BY ITS LOCALIZATION TO SUBNUCLEAR BODIES, A PROCESS THAT IS CONSERVED WITH HUMAN P53. ALTOGETHER, IT IS ANTICIPATED THAT THE OUTCOMES OF OUR INVESTIGATIONS WILL UNCOVER NEW CELLULAR AND MOLECULAR MECHANISMS THAT REGULATE GROWTH AND STRESS RESPONSE, WHICH WILL ULTIMATELY LEAD TO THE BETTER DIAGNOSIS AND TREATMENT OF DEVELOPMENTAL MALFORMATIONS AND CANCER.