Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functi...Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions.Recently,CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers.Although it is still understudied,CCDC3,since its discovery,has been shown to play multiple roles in lipid metabolism,fatty liver,abdominal obesity,anti-inflammation,atherosclerosis,and cancer.This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular(nuclear)functions of CCDC3.We also discuss the possible underlying cellular and molecular mechanisms of CCDC3,the implications for clinical translation,and the remaining puzzles about this special molecule.展开更多
The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus...The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.展开更多
The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis.Here,we identify nerve growth factor receptor(NGFR,p75NTR,or CD271)as a novel negative p73 regulator.p73 activates...The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis.Here,we identify nerve growth factor receptor(NGFR,p75NTR,or CD271)as a novel negative p73 regulator.p73 activates NGFR transcription,which,in turn,promotes p73 degradation in a negative feedback loop.NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells.Surprisingly,we uncover a previously unknown mechanism of NGFR-facilitated p73 degradation through the chaperone-mediated autophagy(CMA)pathway.Collectively,our studies demonstrate a new oncogenic function for NGFR in inactivating p73 activity by promoting its degradation through the CMA.展开更多
基金H.L.and S.X.Z.were supported in part by NIH-NCI grants R01CA095441,R01CA234605,R01CA127724,as well as R21CA272890H.L.was also in part supported by the Reynolds and Ryan Families Endowed Chair fund and the NIH-NCI grant U01CA252965.
文摘Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions.Recently,CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers.Although it is still understudied,CCDC3,since its discovery,has been shown to play multiple roles in lipid metabolism,fatty liver,abdominal obesity,anti-inflammation,atherosclerosis,and cancer.This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular(nuclear)functions of CCDC3.We also discuss the possible underlying cellular and molecular mechanisms of CCDC3,the implications for clinical translation,and the remaining puzzles about this special molecule.
文摘The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.
基金H.L. and S.X.Z.were supported in part by NIH-NCI grants(R01CA095441,R01CA17246 and R01CA127724).
文摘The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis.Here,we identify nerve growth factor receptor(NGFR,p75NTR,or CD271)as a novel negative p73 regulator.p73 activates NGFR transcription,which,in turn,promotes p73 degradation in a negative feedback loop.NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells.Surprisingly,we uncover a previously unknown mechanism of NGFR-facilitated p73 degradation through the chaperone-mediated autophagy(CMA)pathway.Collectively,our studies demonstrate a new oncogenic function for NGFR in inactivating p73 activity by promoting its degradation through the CMA.
