The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

Aylon, Yael; Gershoni, Anat; Rotkopf, Ron; Koh, Alice; Sun, Xiaoguang; Fiel, M. Isabel; Hoshida, Yuujin; Friedman, SL; Johnson, Ralph F.; Oren, Moshe

doi:10.1016/s0959-8049(16)61580-0

Cited by 6 publications

(20 citation statements)

References 15 publications

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“…In a recent research, Lats2 was shown to inhibit SREBPs and suppresses hepatic cholesterol accumulation through a Lats2-p53 axis. 35 Mice harbouring liver-specific Lats2 conditional knockout displayed SREBP activation, leading to spontaneous fatty liver disease. 35 Furthermore, only Lats2, not Lats1, could inhibit SREBPs and suppress hepatic cholesterol accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…35 Mice harbouring liver-specific Lats2 conditional knockout displayed SREBP activation, leading to spontaneous fatty liver disease. 35 Furthermore, only Lats2, not Lats1, could inhibit SREBPs and suppress hepatic cholesterol accumulation. This phenomenon suggests that the directly upstream regulator of YAP can suppress SREBPs independently of Hippo-YAP signalling.…”

Section: Discussionmentioning

confidence: 99%

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A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

Shu

Gao

Zhang

et al. 2019

J Cellular Molecular Medi

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The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Whether the Hippo pathway regulates cell metabolism is unknown. Here, we report that in the nucleus of hepatocytes, Yes‐associated protein(YAP)—the terminal effector of the Hippo pathway—directly interacts with sterol regulatory element binding proteins (SREBP‐1c and SREBP‐2) on the promoters of the fatty acid synthase (FAS) and 30‐hydroxylmethyl glutaryl coenzyme A reductase (HMGCR), thereby stimulating their transcription and promoting hepatocyte lipogenesis and cholesterol synthesis. In diet‐induced diabetic mice, either Lats1 overexpression or YAP knockdown protects against hepatic steatosis and hyperlipidaemia through suppression of the interaction between YAP and SREBP‐1c/SREBP‐2. These results suggest that YAP is a nuclear co‐factor of SREBPs and that the Hippo pathway negatively affects hepatocyte lipogenesis by inhibiting the function of YAP‐SREBP complexes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

Shu

Gao

Zhang

et al. 2019

J Cellular Molecular Medi

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“…Activates p53 in response to mitotic stress 53,[142][143][144]149 Activates p53 in response to oncogenic Ras 117,118 Activates p53 in response to excess cholesterol 156 Activates p53 during mESC differentiation 52 YAP Loss of YAP induces p53 145,147,148 YAP represses ΔNp63 to inhibit lung cancer squamous cells transdifferentiation. 182 YAP-p73 promotes apoptosis 106,108-110, 132-134, 136,183 Yki inactivation induces Dmp53 119 p63 inhibits p73-YAPdependent apoptosis 22,137 YAP-tyr357-p73 is a marker for well differentiated HCC 85 Yki binds Dmp53 to promote apoptosis 131 YAP positively regulates p63 in epidermal stem cells 66 Locus is amplified in p53 null tumors [75][76][77]184,185 YAP positively regulates p63 in airway epithelium 71 p53 and YAP antagonistically regulate FOXM1 [186][187][188] YAP-p63 block differentiation in HNSCC 86 p53 transactivates 14-3-3σ, which inhibits YAP/TAZ 124,125 Binds p63 and prevents its degradation 88,89 YAP and p53 cooperate in apoptosis and senescence [126][127][128] Hyperactivation of YAP/TAZ induces p53 152,154 YAP and mutp53 cooperate in transformation 33,82 Mutp53 induces miRs that tar...…”

Section: Lats2mentioning

confidence: 99%

“…155 LATS2 acts in concert with p53 to inhibit SREBP function ( Figure 2) by binding the ER-tethered precursors of SREBP1 and SREBP2, impeding their processing and quenching the subsequent transcriptional activity of the cleaved, nuclear SREBPs. 156 Expression of hepatic Lats2 is required to avoid fatty liver disease and for induction of a p53 pro-apoptotic response when mice are challenged with excess dietary cholesterol. 156 Conversely, forced expression of SREBP1 in mouse liver leads to p53 activation.…”

Section: Metabolic Homeostasismentioning

confidence: 99%

“…156 Expression of hepatic Lats2 is required to avoid fatty liver disease and for induction of a p53 pro-apoptotic response when mice are challenged with excess dietary cholesterol. 156 Conversely, forced expression of SREBP1 in mouse liver leads to p53 activation. 157 Thus, together, p53 and LATS2 function to maintain appropriate levels of SREBP activity and cholesterol homeostasis within the liver.…”

Section: Metabolic Homeostasismentioning

confidence: 99%

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p53 shades of Hippo

2017

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The three p53 family members, p53, p63 and p73, are structurally similar and share many biochemical activities. Yet, along with their common fundamental role in protecting genomic fidelity, each has acquired distinct functions related to diverse cell autonomous and non-autonomous processes. Similar to the p53 family, the Hippo signaling pathway impacts a multitude of cellular processes, spanning from cell cycle and metabolism to development and tumor suppression. The core Hippo module consists of the tumor-suppressive MST-LATS kinases and oncogenic transcriptional co-effectors YAP and TAZ. A wealth of accumulated data suggests a complex and delicate regulatory network connecting the p53 and Hippo pathways, in a highly context-specific manner. This generates multiple layers of interaction, ranging from interdependent and collaborative signaling to apparent antagonistic activity. Furthermore, genetic and epigenetic alterations can disrupt this homeostatic network, paving the way to genomic instability and cancer. This strengthens the need to better understand the nuances that control the molecular function of each component and the cross-talk between the different components. Here, we review interactions between the p53 and Hippo pathways within a subset of physiological contexts, focusing on normal stem cells and development, as well as regulation of apoptosis, senescence and metabolism in transformed cells.

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Lipid metabolism in cancer progression and therapeutic strategies

Zou

Shen

et al. 2020

MedComm

127

113

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Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune‐associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

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The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

Cited by 6 publications

References 15 publications

A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

p53 shades of Hippo

Lipid metabolism in cancer progression and therapeutic strategies

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