Proapoptotic function of the retinoblastoma tumor suppressor protein.
The retinoblastoma protein (pRB) tumor suppressor blocks cell proliferation by repressing the E2F transcription factors. This inhibition is relieved through mitogen-induced phosphorylation of pRB, triggering E2F release and activation of cell-cycle genes. E2F1 can also activate proapoptotic genes in response to genotoxic or oncogenic stress. However, pRB's role in this context has not been established. Here we show that DNA damage and E1A-induced oncogenic stress promote formation of a pRB-E2F1 complex even in proliferating cells. Moreover, pRB is bound to proapoptotic promoters that are transcriptionally active, and pRB is required for maximal apoptotic response in vitro and in vivo. Together, these data reveal a direct role for pRB in the induction of apoptosis in response to genotoxic or oncogenic stress.
Ianari
Alessandra
A
David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
Natale
Tiziana
T
Calo
Eliezer
E
Ferretti
Elisabetta
E
Alesse
Edoardo
E
Screpanti
Isabella
I
Haigis
Kevin
K
Gulino
Alberto
A
Lees
Jacqueline A
JA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein