CellCycleRegulation-PartII

Dhyan Chandra, Ph.D.Department of Pharmacology and TherapeuticsL4-305, Center for Genetics and Pharmacology

Roswell Park Cancer InstituteElm and Carlton Streets, Buffalo

Topics to be discussed • Recap of the last cell cycle lecture • Alteration of cellular signaling in cancer • Cell cycle and apoptosis • Differences between cancer and normal cells • Cell cycle regulation in lung carcinogenesis • The role of ROS in cell cycle

Cyclinexpressionduringcellcycle

cyclinB

Controlofcyclinlevelsduringthecellcycle

(A-CDK1) (B-CDK1)

Controlofcyclinadvancebyextracellularsignals

Positive-feedbackloopsandirreversibilityofcellcycleadvance

Positive-feedbackloopsandirreversibilityofcellcycleadvance

Alterationofcellularsignalingincancer

ControlofcyclinDlevels

ControlofcyclinD1levelsbyRas

ActionofMyconcellcycle

ActionofMyc-ER(estrogenreceptor)oncellcycle

MycinhibitscelldifferentiationbyID(inhibitorofdifferentiation)

PerturbationoftheR-pointtransitioninhumantumorsRed:favorscellcycle Blue:inhibitscellcycle Gray:notknowntochangecellcycle

Regulationandactivitiesofp53andE2F

IaquintaandLeesCurrentOpinioninCellBiology2007

E2Ftargetsareshowninred

p53targetsareshowninblue

TargetsforE2Fandp53-purple

E2F1regulatesp53andthusapoptosis

Differencesbetweencancerandnormalcells

Contrasting schemes of the proposed response of normal and cancer cells to mitogens.

Zwang Y et al. Cancer Res 2012;72:1051-1054

Cellcycleregulationinlungcarcinogenesis

EyminandGazzeriCellCycle2009

Darkgrey:overexpressedLightgrey:lossofexpression

Abnormalitiesofcellcycleregulatorsinhumanlungtumors

EyminandGazzeriCellCycle2009

Alterationsincomponentsofcellcyclecheckpointsinlungtumors

EyminandGazzeriCellCycle2009

AlterationsoftheG1/StransitionregulatorsinNSCLCvsSCLC

TheroleofROSincellcycle

Mitochondria

Mitochondrial respiratory chain

KobayashiandSuda,jCellPhysiol2011

WangandYi,CancerBiologyandTherapy2008