PMID- 28013293 OWN - NLM STAT- MEDLINE DCOM- 20170920 LR - 20211204 IS - 1460-2083 (Electronic) IS - 0964-6906 (Linking) VI - 26 IP - 2 DP - 2017 Jan 15 TI - Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex. PG - 407-419 LID - 10.1093/hmg/ddw397 [doi] AB - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma-derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples. TSC1/TSC2 complex upregulation of OPN expression is mediated by transcription factor SOX9 in an mTOR-independent manner. Moreover, ablation of OPN by deficient TSC1/TSC2 complex contributed to inactivation of AKT in TSC cells. Lastly, the abundance of OPN dictated the potency of cell proliferation and tumour development. Therefore, loss of TSC1/TSC2 complex led to mTOR-independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade. We suggest that the decreased SOX9-OPN-AKT signalling pathway safeguard against the development of malignant tumours in TSC patients. CI - (c) The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Jin, Fuquan AU - Jin F AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China. FAU - Jiang, Keguo AU - Jiang K AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China. AD - Department of Nephrology, The Third Affiliated Hospital, Anhui Medical University, Hefei, People's Republic of China. FAU - Ji, Shuang AU - Ji S AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China. AD - Department of Respiratory Medicine, The First Affiliated Hospital, Anhui Medical University, Hefei, People's Republic of China. FAU - Wang, Li AU - Wang L AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China. FAU - Ni, Zhaofei AU - Ni Z AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China. FAU - Huang, Fuqiang AU - Huang F AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and. FAU - Li, Chunjia AU - Li C AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and. FAU - Chen, Rongrong AU - Chen R AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and. FAU - Zhang, Hongbing AU - Zhang H AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China and. FAU - Hu, Zhongdong AU - Hu Z AD - Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People's Republic of China. FAU - Zha, Xiaojun AU - Zha X AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China. AD - Institute of Dermatology, Anhui Medical University, Hefei, People's Republic of China. LA - eng PT - Journal Article PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 0 (SOX9 Transcription Factor) RN - 0 (Sox9 protein, mouse) RN - 0 (TSC1 protein, human) RN - 0 (TSC2 protein, human) RN - 0 (Tsc1 protein, mouse) RN - 0 (Tsc1 protein, rat) RN - 0 (Tsc2 protein, mouse) RN - 0 (Tsc2 protein, rat) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 106441-73-0 (Osteopontin) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Cell Proliferation/genetics MH - Fibroblasts/metabolism/pathology MH - Gene Expression Regulation MH - Humans MH - Mice MH - Neoplasms/genetics/pathology MH - Oncogene Protein v-akt/*genetics MH - Osteopontin/*genetics MH - Rats MH - SOX9 Transcription Factor/*genetics MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*genetics MH - Tuberous Sclerosis/*genetics/pathology MH - Tuberous Sclerosis Complex 1 Protein MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/*genetics EDAT- 2016/12/26 06:00 MHDA- 2017/09/21 06:00 CRDT- 2016/12/26 06:00 PHST- 2016/08/04 00:00 [received] PHST- 2016/11/17 00:00 [accepted] PHST- 2016/12/26 06:00 [pubmed] PHST- 2017/09/21 06:00 [medline] PHST- 2016/12/26 06:00 [entrez] AID - ddw397 [pii] AID - 10.1093/hmg/ddw397 [doi] PST - ppublish SO - Hum Mol Genet. 2017 Jan 15;26(2):407-419. doi: 10.1093/hmg/ddw397.