Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determina...Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of odontogenic tissues. Multiple signaling molecules, including BMPs, FGFs, Shh, and Wnt proteins, have been implicated in mediating these tissue interactions. Transcription factors participate in epithelial-mesenchymal interactions via linking the signaling loops between tissue layers by responding to inductive signals and regulating the expression of other signaling molecules. Adult stem cells are highly plastic and multipotent. These cells including dental pulp stem cells and bone marrow stromal cells could be reprogrammed into odontogenic fate and participated in tooth formation. Recent progress in the studies of molecular basis of tooth development, adult stem cell biology, and regene- ration will provide fundamental knowledge for the realization of human tooth regeneration in the near future.展开更多
POU transcription factor OCT4 not only plays an essential role in maintaining the pluripotent and self-renewing state of embryonic stem （ES） cells but also acts as a cell fate determinant through a gene dosage effec...POU transcription factor OCT4 not only plays an essential role in maintaining the pluripotent and self-renewing state of embryonic stem （ES） cells but also acts as a cell fate determinant through a gene dosage effect. However, the molecular mechanisms that control the intracellular OCT4 protein level remain elusive. Here, we report that human WWP2, an E3 ubiquitin （Ub）-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo. We first demonstrated that endogenous OCT4 in hu- man ES cells can be post-translationally modified by Ub. Furthermore, we found that WWP2 promoted degradation of OCT4 through the 26S proteasome in a dosage-dependent manner, and the active site cysteine residue of WWP2 was required for both its enzymatic activity and proteolytic effect on OCT4. Remarkably, our data show that the en- dogenous OCT4 protein level was significantly elevated when WWP2 expression was downregulated by specific RNA interference （RNAi）, suggesting that WWP2 is an important regulator for maintaining a proper OCT4 protein level in human ES cells. Moreover, northern blot analysis showed that the WWP2 transcript was widely present in diverse human tissues/organs and highly expressed in undifferentiated human ES cells. However, its expression level was quickly decreased after human ES cells differentiated, indicating that WWP2 expression might be developmentally regulated. Our findings demonstrate that WWP2 is an important regulator of the OCT4 protein level in human ES cells.展开更多
Mesenchymal stem cells （MSCs） are considered as the developmental origin of multiple Uneage cells including osteocytes, adipocytes, and muscle cells. Previous studies demonstrated that the PH domain.containing prote...Mesenchymal stem cells （MSCs） are considered as the developmental origin of multiple Uneage cells including osteocytes, adipocytes, and muscle cells. Previous studies demonstrated that the PH domain.containing protein CKIP-1 plays an important role in the devel- opment of osteobiasts and cardiomyocytes. However, whether CKIP-1 is involved in the generation of adipocytes as weU as the MSC differentiation remains unknown. Here we show that CKIP-1 is a novel regulator of MSCs differentiating into adipocytes. MSCs derived from CKIP-l-deficient mice display enhanced adipogenesis upon induction. Further analysis showed that CKIP-1 interacts with the histone deacetylase HDAC1 in the nucleus and inhibits the transcription of CCAAT/enhancer-binding protein α （C/EBPcx）, which is a crucial adipogenic transcription factor. Ectopic expression of CKI P-1 in a MSC-Uke cell line C3H/10T1/2 reduced the gener- ation of adipocytes due to suppression of adipogenic factors, including C/EBPα. Moreover, CKI P-l-deficient mice showed an increase in body weight and white adipose tissue gains when fed on a high-fat diet. Collectively, these results suggest that CKIP-1 is a novel inhibitor of MSC-originated adipogenesis by enhancing HDACl-associated repression of C/EBPα.展开更多
基金The studies described here from the authors'laborato-ries were supported by grants from the NIH,NSF,and Louisiana Board of Regents to Yi Ping CHEN,and Na-tional Natural Science Foundation of China(No.30270652)Fujian Provincial Department of Science and Technology(No.2002I006),China to Yan Ding ZHANG.
文摘Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of odontogenic tissues. Multiple signaling molecules, including BMPs, FGFs, Shh, and Wnt proteins, have been implicated in mediating these tissue interactions. Transcription factors participate in epithelial-mesenchymal interactions via linking the signaling loops between tissue layers by responding to inductive signals and regulating the expression of other signaling molecules. Adult stem cells are highly plastic and multipotent. These cells including dental pulp stem cells and bone marrow stromal cells could be reprogrammed into odontogenic fate and participated in tooth formation. Recent progress in the studies of molecular basis of tooth development, adult stem cell biology, and regene- ration will provide fundamental knowledge for the realization of human tooth regeneration in the near future.
基金Acknowledgments We are grateful to Dr DA Melton （Harvard University） for shar- ing his human ES cells with us. The study was supported by grants from the National High Technology Research and Development Program of China （2006CB943900）, the National Natural Science Foundation of China （General Program, 30500088）, the Shang- hai Jiao Tong University School of Medicine, and the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The study was also supported by the Shanghai Leading Academic Deciline Project （S30201）.
文摘POU transcription factor OCT4 not only plays an essential role in maintaining the pluripotent and self-renewing state of embryonic stem （ES） cells but also acts as a cell fate determinant through a gene dosage effect. However, the molecular mechanisms that control the intracellular OCT4 protein level remain elusive. Here, we report that human WWP2, an E3 ubiquitin （Ub）-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo. We first demonstrated that endogenous OCT4 in hu- man ES cells can be post-translationally modified by Ub. Furthermore, we found that WWP2 promoted degradation of OCT4 through the 26S proteasome in a dosage-dependent manner, and the active site cysteine residue of WWP2 was required for both its enzymatic activity and proteolytic effect on OCT4. Remarkably, our data show that the en- dogenous OCT4 protein level was significantly elevated when WWP2 expression was downregulated by specific RNA interference （RNAi）, suggesting that WWP2 is an important regulator for maintaining a proper OCT4 protein level in human ES cells. Moreover, northern blot analysis showed that the WWP2 transcript was widely present in diverse human tissues/organs and highly expressed in undifferentiated human ES cells. However, its expression level was quickly decreased after human ES cells differentiated, indicating that WWP2 expression might be developmentally regulated. Our findings demonstrate that WWP2 is an important regulator of the OCT4 protein level in human ES cells.
文摘Mesenchymal stem cells （MSCs） are considered as the developmental origin of multiple Uneage cells including osteocytes, adipocytes, and muscle cells. Previous studies demonstrated that the PH domain.containing protein CKIP-1 plays an important role in the devel- opment of osteobiasts and cardiomyocytes. However, whether CKIP-1 is involved in the generation of adipocytes as weU as the MSC differentiation remains unknown. Here we show that CKIP-1 is a novel regulator of MSCs differentiating into adipocytes. MSCs derived from CKIP-l-deficient mice display enhanced adipogenesis upon induction. Further analysis showed that CKIP-1 interacts with the histone deacetylase HDAC1 in the nucleus and inhibits the transcription of CCAAT/enhancer-binding protein α （C/EBPcx）, which is a crucial adipogenic transcription factor. Ectopic expression of CKI P-1 in a MSC-Uke cell line C3H/10T1/2 reduced the gener- ation of adipocytes due to suppression of adipogenic factors, including C/EBPα. Moreover, CKI P-l-deficient mice showed an increase in body weight and white adipose tissue gains when fed on a high-fat diet. Collectively, these results suggest that CKIP-1 is a novel inhibitor of MSC-originated adipogenesis by enhancing HDACl-associated repression of C/EBPα.
