bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022‒12‒04
seven papers selected by
Marti Cadena Sandoval
Columbia University
  1. [Analysis of TSC2 gene variant in a neonate with tuberous sclerosis complex].
  2. Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions.
  3. Qualitative and quantitative evaluation for the heterogeneity of cortical tubers using structural imaging and diffusion-weighted imaging to predict the epileptogenicity in tuberous sclerosis complex patients.
  4. Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.
  5. GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila.
  6. The human LAT1-4F2hc (SLC7A5 - SLC3A2) transporter complex: physiological and pathophysiological implications.
  7. Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development.
  1. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Dec 10. 39(12): 1390-1392
    [Analysis of TSC2 gene variant in a neonate with tuberous sclerosis complex].
    Canyang Zhan, Lihua Chen.
      OBJECTIVE: To explore the clinical characteristics and genetic variant in a neonate with tuberous sclerosis complex (TSC).METHODS: Clinical data of the neonate was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to next-generation sequencing (NGS).
    RESULTS: The child was noted to have yellowish hair upon birth. NGS revealed that he has harbored a heterozygous c.3914del (p.P1305Rfs*20) frameshifting variant of the TSC2 gene. The variant has probably caused premature termination of translation, resulting in a truncated protein.
    CONCLUSION: Yellowish hair has rarely been described as the first manifestation of TSC. The c.3914del (p.P1305Rfs*20) variant of the TSC2 gene probably underlay the TSC in this patient.
    DOI:  https://doi.org/10.3760/cma.j.cn511374-20211016-00820
  2. Pediatr Nephrol. 2022 Nov 29.
    Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions.
    Sebastian Gallo-Bernal, Aoife Kilcoyne, Michael S Gee, Elahna Paul.
      Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an estimated incidence of one in 5000 to 10,000 live births worldwide. Two million people of all races and genders are estimated to have TSC secondary to mutations in one of two tumor suppressor genes, TSC1 or TSC2. The respective TSC1 and 2 gene products - hamartin and tuberin - form cytoplasmic heterodimers that inhibit mTOR-mediated cell growth and division. When mTOR inhibition is lost, people with TSC develop characteristic and usually benign tumors in various organ systems. Kidney tumors and cysts are common, particularly in the setting of TSC2 gene mutations. In most TSC patients, the number of kidney cysts is limited, their morphology is simple, their size is small, and their clinical significance is negligible. In some, cyst morphology progresses from simple to complex with the risk of malignant transformation. In others, aggressive accumulation and growth of kidney cysts can cause hypertension, impaired kidney function, and progression to kidney failure. This educational review summarizes current knowledge and remaining open questions regarding cystic kidney disease in TSC, emphasizing detection, classification, surveillance, and treatment options.
    Keywords:  Contiguous gene syndrome; Renal cell carcinoma; Renal cyst; TSC; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1007/s00467-022-05820-x
  3. Neuroradiology. 2022 Dec 01.
    Qualitative and quantitative evaluation for the heterogeneity of cortical tubers using structural imaging and diffusion-weighted imaging to predict the epileptogenicity in tuberous sclerosis complex patients.
    Akira Yogi, Yoko Hirata, Michael Linetsky, Benjamin M Ellingson, Noriko Salamon.
      PURPOSE: We aimed to evaluate whether the heterogeneity of tuber imaging features, evaluated on the structural imaging and apparent diffusion coefficient (ADC) map, can facilitate detecting epileptogenic tubers before surgery in tuberous sclerosis complex (TSC) patients.METHODS: Twenty-three consecutive patients, who underwent tuber resection at our institute, were retrospectively selected. A total of 125 tubers (39 epileptogenic, 86 non-epileptogenic) were used for the analysis. Tuber heterogeneity was evaluated, using a 5-point visual scale and standard deviation of ADC values (ADCsd). A 5-point visual scale reflected the degree of T1/T2 prolongation, presence of internal cystic degeneration, and their spatial distribution within the tuber. These results were statistically compared between epileptogenic and non-epileptogenic groups, and their performance in predicting the epileptogenicity was also evaluated by receiver operating characteristic (ROC) analysis.
    RESULTS: A 5-point visual scale demonstrated that more heterogeneous tubers were significantly more epileptogenic (p < 0.001). Multiplicity of internal cystic degeneration moderately correlated with epileptogenicity (p < 0.03) based on the comparison between class 4 and class 5 tubers. ADCsd was significantly higher in epileptogenic tubers (p < 0.001). ROC curves revealed that a 5-point visual scale demonstrated higher area under the curve (AUC) value than ADCsd (0.75 and 0.72, respectively).
    CONCLUSION: Tuber heterogeneity may help identify the epileptogenic tubers in presurgical TSC patients. Visual assessment and standard deviation of ADC value, which are easier to implement in clinical use, may be a useful tool predicting epileptogenic tubers, improving presurgical clinical management for TSC patients with intractable epilepsy.
    Keywords:  ADC; Cystic; Epileptogenicity; Heterogeneity; Tuber
    DOI:  https://doi.org/10.1007/s00234-022-03094-6
  4. Theranostics. 2022 ;12(18): 7903-7919
    Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.
    Yuan-Deng Luo, Xiao-Yu Liu, Lei Fang, Hong-Qiang Yu, Yu-Jun Zhang, Min Chen, Lei-Da Zhang, Chuan-Ming Xie.
      Background & Aims: Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC). Mutant Kras could induce aggressive HCCs. Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs. Methods: We generated transgenic mice in which hepatocytic mTOR was hyperactivated through Tsc1 insufficiency with or without oncogenic KrasG12D. Bioinformatics and gain- or loss-of-function studies were used to illustrate the mechanisms underlying oncogenic pathway alterations. Transcriptional profiling was used to identify biomarker for the subtype of HCC. The therapeutic efficacy of targeting mTOR was tested in a liver orthotropic homogeneous murine model. Results: Oncogenic KrasG12D facilitated mTOR activation via the Mek/Erk/ROS axis, leading to HCC tumorigenesis and metastasis. Inhibition of Mek/Erk enhanced the anticancer effect of mTOR inhibitor via reduction of mTOR activity. Paternally expressed 3 (PEG3) was responsible for Kras/Erk- and mTOR-driven HCC. Elevated PEG3 protein interacted with STAT3 and promoted its transcriptional activity, resulting in the upregulation of proliferation- and metastasis-related proteins. Targeting mTOR significantly inhibited these actions in vitro and in vivo. Moreover, in clinical samples, PEG3 was identified as a new poor prognostic marker for HCC patients with Kras/Erk and mTOR hyperactivation. Conclusion: These findings reveal the underlying mechanism of hepatocytic Kras/Erk-driven mTOR activation and its downstream targets (PEG3 and STAT3) in HCC, identify PEG3 as a new prognostic biomarker for HCC with Kras/Erk and mTOR hyperactivation, and provide a potential therapeutic strategy for this subset of HCC patients.
    Keywords:  Cancer therapy; Kras/Mek/Erk; PEG3; STAT3; hepatocellular carcinoma
    DOI:  https://doi.org/10.7150/thno.76873
  5. Cell Death Dis. 2022 Nov 27. 13(11): 1003
    GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila.
    Anna Frappaolo, Angela Karimpour-Ghahnavieh, Giuliana Cesare, Stefano Sechi, Roberta Fraschini, Thomas Vaccari, Maria Grazia Giansanti.
      The oncoprotein GOLPH3 (Golgi phosphoprotein 3) is an evolutionarily conserved phosphatidylinositol 4-phosphate effector, mainly localized to the Golgi apparatus, where it supports organelle architecture and vesicular trafficking. Overexpression of human GOLPH3 correlates with poor prognosis in several cancer types and is associated with enhanced signaling downstream of mTOR (mechanistic target of rapamycin). However, the molecular link between GOLPH3 and mTOR remains elusive. Studies in Drosophila melanogaster have shown that Translationally controlled tumor protein (Tctp) and 14-3-3 proteins are required for organ growth by supporting the function of the small GTPase Ras homolog enriched in the brain (Rheb) during mTORC1 (mTOR complex 1) signaling. Here we demonstrate that Drosophila GOLPH3 (dGOLPH3) physically interacts with Tctp and 14-3-3ζ. RNAi-mediated knockdown of dGOLPH3 reduces wing and eye size and enhances the phenotypes of Tctp RNAi. This phenotype is partially rescued by overexpression of Tctp, 14-3-3ζ, or Rheb. We also show that the Golgi localization of Rheb in Drosophila cells depends on dGOLPH3. Consistent with dGOLPH3 involvement in Rheb-mediated mTORC1 activation, depletion of dGOLPH3 also reduces levels of phosphorylated ribosomal S6 kinase, a downstream target of mTORC1. Finally, the autophagy flux and the expression of autophagic transcription factors of the TFEB family, which anti correlates with mTOR signaling, are compromised upon reduction of dGOLPH3. Overall, our data provide the first in vivo demonstration that GOLPH3 regulates organ growth by directly associating with mTOR signaling proteins.
    DOI:  https://doi.org/10.1038/s41419-022-05438-9
  6. Basic Clin Pharmacol Toxicol. 2022 Dec 02.
    The human LAT1-4F2hc (SLC7A5 - SLC3A2) transporter complex: physiological and pathophysiological implications.
    Jennifer Kahlhofer, David Teis.
      LAT1 and 4F2hc form a heterodimeric membrane protein complex, which functions as one of the best characterized amino acid transporters. Since LAT1 - 4F2hc is required for the efficient uptake of essential amino acids and hormones, it promotes cellular growth, in part, by stimulating mTORC1 (mechanistic target of rapamycin complex 1) signalling and by repressing the integrated stress response (ISR). Gain - or loss of LAT1 - 4F2hc function is associated with cancer, diabetes, immunological - and neurological diseases. Hence, LAT1 - 4F2hc represents an attractive drug target for disease treatment. Specific targeting of LAT1 - 4F2hc will be facilitated by the increasingly detailed understanding of its molecular architecture, which provides important concepts for its function and regulation. Here, we summarize (i) structural insights that help to explain how LAT1 and 4F2hc assemble to transport amino acids across membranes, (ii) the role of LAT1-4F2hc in key metabolic signalling pathways, and (iii) how derailing these processes could contribute to diseases.
    Keywords:  4F2hc; LAT1; disease; integrated stress response; mTORC1
    DOI:  https://doi.org/10.1111/bcpt.13821
  7. Development. 2022 Nov 28. pii: dev.201286. [Epub ahead of print]
    Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development.
    Xiangxing Kong, Xin Shu, Jiachuan Wang, Dandan Liu, Yingchun Ni, Weiqi Zhao, Lebo Wang, Zhihua Gao, Jiadong Chen, Bing Yang, Xing Guo, Zhiping Wang.
      Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders (NDDs). Here, we discover that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures, and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells (NPCs) and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitinates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of NPCs. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.
    Keywords:  KLHL22; Neural precursor cell; Neurogenesis; UBE4B E3/E4 ubiquitin ligase; mTOR signaling
    DOI:  https://doi.org/10.1242/dev.201286
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