Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain.
BACKGROUND
The polycomb group (PcG) protein BMI1 is an important regulator of development. Additionally, aberrant expression of BMI1 has been linked to cancer stem cell phenotype and oncogenesis. In particular, its overexpression has been found in several human malignancies including breast cancer. Despite its established role in stem cell maintenance, cancer and development, at present not much is known about the functional domains of BMI1 oncoprotein. In the present study, we carried out a deletion analysis of BMI1 to identify its negative regulatory domain.


RESULTS
We report that deletion of the C-terminal domain of BMI1, which is rich in proline-serine (PS) residues and previously described as PEST-like domain, increased the stability of BMI1, and promoted its pro-oncogenic activities in human mammary epithelial cells (HMECs). Specifically, overexpression of a PS region deleted mutant of BMI1 increased proliferation of HMECs and promoted an epithelial-mesenchymal transition (EMT) phenotype in the HMECs. Furthermore, when compared to the wild type BMI1, exogenous expression of the mutant BMI1 led to a significant downregulation of p16INK4a and an efficient bypass of cellular senescence in human diploid fibroblasts.


CONCLUSIONS
In summary, our data suggest that the PS domain of BMI1 is involved in its stability and that it negatively regulates function of BMI1 oncoprotein. Our results also suggest that the PS domain of BMI1 could be targeted for the treatment of proliferative disorders such as cancer and aging.
Yadav
Ajay K
AK
Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
Sahasrabuddhe
Anagh A
AA
Dimri
Manjari
M
Bommi
Prashant V
PV
Sainger
Rachana
R
Dimri
Goberdhan P
GP
D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D006207:Half-Life; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion
C069077:BMI1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1