Balancing proliferation and apoptosis in vivo: the Goldilocks theory of E2F/DP action.
Stimulation of both proliferation and apoptosis by E2F-1 provides a mechanistic basis for how E2F-1 functions as an oncogene and a tumor suppressor in vivo. In each normal tissue, a precise balance of proliferation versus apoptosis must be maintained, and in many tissues this appears to be controlled by E2F-1 levels. Presumably, variable expression of all E2F family members in each tissue dictates a tissue-specific sensitivity to loss or overexpression of any one family member. At sites where E2F-1 contributes mainly to proliferation and p53 levels remain low, loss of E2F-1 expression may lead to tissue atrophy and overexpression may lead to hyperplasia or tumors. Hence, E2F-1 would act as an oncogene. At other sites where E2F-1 levels induce p19, which stabilizes p53 leading to apoptosis, E2F-1 overexpression may lead to tissue atrophy and loss of expression may lead to hyperplasia or tumors. And thus, E2F-1 would act as a tumor suppressor. Perhaps it is the unique property of E2F-1 within the E2F family to stimulate both proliferation and apoptosis which makes it a bimodal switch that pRB must control so carefully. It is a delicate equilibrium that must be maintained throughout embryonic development and adult life. However, it is easy to envision that mutations which deregulate other E2F family members and which ultimately lead to changes in E2F-1 levels could lead to similar growth aberrations. In summary, although pRB interacts with numerous transcription factors, pRB minimally must restrain the E2F/DP transcription factor family to prevent the cell cycle from whirling onwards out of control.
Yamasaki
L
L
Columbia University, Department of Biological Sciences, New York, NY 10027, USA. ly63@columbia.edu
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C117145:DP-interacting protein, mouse; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53