Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation.
Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN(+/+) transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation.
Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
M
M
Calao
E O
EO
Sekyere
H J
HJ
Cui
B B
BB
Cheung
W D
WD
Thomas
J
J
Keating
J B
JB
Chen
A
A
Raif
K
K
Jankowski
N P
NP
Davies
M V
MV
Bekkum
B
B
Chen
O
O
Tan
T
T
Ellis
M D
MD
Norris
M
M
Haber
E S
ES
Kim
J M
JM
Shohet
T N
TN
Trahair
T
T
Liu
B J
BJ
Wainwright
H F
HF
Ding
G M
GM
Marshall
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009373:Neoplasms, Germ Cell and Embryonal / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*; D054875:Ubiquitination
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025821:Polyubiquitin; D063150:Polycomb Repressive Complex 1; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex