Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the...Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the nucleus to form a PIP_(n)-p53 signalosome that modulates nuclear AKT activation and downstream signaling,thereby influencing cancer cell survival and motility.This review examines recent insights into nuclear PIP_(n)signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_(n)s interact with p53 to form signalosomes that affect cell motility.We emphasize the critical role of PIP_(n)in stabilizing p53 and activating de novo nuclear AKT signaling,which subsequently modulates key motility-related pathways.Understanding the unique operation and function of the PIP_(n)-p53 signalosome in nuclear phosphatidylinositol 3-kinase(PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.展开更多
Osteoporosis(OP)is a systemic skeletal disease that primarily affects the elderly population,which greatly increases the risk of fractures.Here we report that Kindlin-2 expression in adipose tissue increases during ag...Osteoporosis(OP)is a systemic skeletal disease that primarily affects the elderly population,which greatly increases the risk of fractures.Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass.Kindlin-2 specific deletion(K2KO)controlled by Adipoq-Cre mice or adipose tissue-targeting AAV(AAV-Rec2-CasRx-sgK2)significantly increases bone mass.Mechanistically,Kindlin-2 promotes peroxisome proliferator-activated receptor gamma(PPARγ)activation and downstream fatty acid binding protein 4(FABP4)expression through stabilizing fatty acid synthase(FAS),and increased FABP4 inhibits insulin expression and decreases bone mass.Kindlin-2 inhibition results in accelerated FAS degradation,decreased PPARγactivation and FABP4 expression,and therefore increased insulin expression and bone mass.Interestingly,we find that FABP4 is increased while insulin is decreased in serum of OP patients.Increased FABP4 expression through PPARγactivation by rosiglitazone reverses the high bone mass phenotype of K2KO mice.Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice.Collectively,our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.展开更多
基金supported by grants JCYJ20220818102611025 and RCYX20210706092040044 from the Science and Technology Foundation of Shenzhengrant 82071193 from the National Natural Science Foundation of China+4 种基金grant 0920220233 from the Guangdong Zhujiang Programsupported by grant JCYJ20240813094605008 from the Shenzhen Natural Science Foundationgrant D2301007 from the Shenzhen Medical Research Fundgrant 2023A1515110237 from the Guangdong Province Basic and Applied Basic Research Foundationgrant 32400577 from the National Natural Science Foundation of China。
文摘Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the nucleus to form a PIP_(n)-p53 signalosome that modulates nuclear AKT activation and downstream signaling,thereby influencing cancer cell survival and motility.This review examines recent insights into nuclear PIP_(n)signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_(n)s interact with p53 to form signalosomes that affect cell motility.We emphasize the critical role of PIP_(n)in stabilizing p53 and activating de novo nuclear AKT signaling,which subsequently modulates key motility-related pathways.Understanding the unique operation and function of the PIP_(n)-p53 signalosome in nuclear phosphatidylinositol 3-kinase(PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.
基金partially came from National Natural Science Foundation of China Grants (82022047 and 81972100)the National Key Research and Development Program of China Grants (2019YFA0906001)Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018,China)。
文摘Osteoporosis(OP)is a systemic skeletal disease that primarily affects the elderly population,which greatly increases the risk of fractures.Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass.Kindlin-2 specific deletion(K2KO)controlled by Adipoq-Cre mice or adipose tissue-targeting AAV(AAV-Rec2-CasRx-sgK2)significantly increases bone mass.Mechanistically,Kindlin-2 promotes peroxisome proliferator-activated receptor gamma(PPARγ)activation and downstream fatty acid binding protein 4(FABP4)expression through stabilizing fatty acid synthase(FAS),and increased FABP4 inhibits insulin expression and decreases bone mass.Kindlin-2 inhibition results in accelerated FAS degradation,decreased PPARγactivation and FABP4 expression,and therefore increased insulin expression and bone mass.Interestingly,we find that FABP4 is increased while insulin is decreased in serum of OP patients.Increased FABP4 expression through PPARγactivation by rosiglitazone reverses the high bone mass phenotype of K2KO mice.Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice.Collectively,our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.
