Peroxisome-proliferator-activated receptor-binding protein (PBP) is essential for the growth of active Notch4-immortalized mammary epithelial cells by activating SOX10 expression.
PBP (peroxisome-proliferator-activated receptor-binding protein) [Med1 (mediator 1)/TRAP220 (thyroid-hormone-receptor-associated protein 220)] is essential for mammary gland development. We established a mammary epithelial cell line with a genotype of PBPLoxP/LoxP by expressing an active form of Notch4. Null mutation of PBP caused severe growth inhibition of the Notch4-immortalized mammary cells. We found that truncated PBP without the two LXXLL motifs could reverse the growth inhibition due to the deficiency of endogenous PBP, indicating that signalling through nuclear receptors is unlikely to be responsible for the growth inhibition as the result of PBP deficiency. Loss of PBP expression was shown to completely ablate the expression of SOX10 [Sry-related HMG (high-mobility group) box gene 10]. The re-expression of SOX10 was capable of reversing the growth inhibition due to PBP deficiency, whereas suppressed expression of SOX10 inhibited the growth of Notch4-immortalized mammary cells. Further studies revealed PBP is directly recruited to the enhancer of the SOX10 gene, indicating that SOX10 is a direct target gene of PBP. We conclude that PBP is essential for the growth of Notch4-immortalized mammary cells by activating SOX10 expression, providing a potential molecular mechanism through which PBP regulates the growth of mammary stem/progenitor cells.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, U.S.A.
Yiwei Tony
YT
Zhu
Yuzhi
Y
Jia
Liping
L
Hu
Chao
C
Qi
Megana K
MK
Prasad
Andrew S
AS
McCallion
Yi-Jun
YJ
Zhu
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology*; D008321:Mammary Glands, Animal / Q000166:cytology*; D056913:Mediator Complex Subunit 1 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D055757:SOXE Transcription Factors / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology; D015533:Transcriptional Activation / Q000502:physiology*
D056913:Mediator Complex Subunit 1; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D055757:SOXE Transcription Factors; C073572:Notch4 protein, mouse