Nicastrin expression in mouse peripheral tissues is not co‐ordinated with presenilin and is high in muscle

Ilaya, Nancy T.; Evin, Geneviève; Masters, Colin L.; Culvenor, Janetta G.

doi:10.1111/j.1471-4159.2004.02718.x

Cited by 17 publications

(7 citation statements)

References 52 publications

(113 reference statements)

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“…In silico transcriptome analysis utilizing the GeneSapiens database gave further support to our observation. This finding was unexpected in the light of previous studies showing differential expression of PS1/PS2 and Aph1a/Aph1b among various tissues [11,12,14-16] and the compensatory expression of other members of PS or Aph1 families when the endogenous expression of their counterparts have been artificially suppressed [10,23,29]. However, our results are in line with the studies showing joint expression levels for the various γ-secretase components [12,18,54].…”

Section: Discussioncontrasting

confidence: 61%

γ-Secretase Components as Predictors of Breast Cancer Outcome

et al. 2013

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γ-secretase is a large ubiquitously expressed protease complex composed of four core subunits: presenilin, Aph1, PEN-2, and nicastrin. The function of γ-secretase in the cells is to proteolytically cleave various proteins within their transmembrane domains. Presenilin and Aph1 occur as alternative variants belonging to mutually exclusive γ-secretase complexes and providing the complexes with heterogeneous biochemical and physiological properties. γ-secretase is proposed to have a role in the development and progression of cancer and γ-secretase inhibitors are intensively studied for their probable anti-tumor effects in various types of cancer models. Here, we for the first time determined mRNA expression levels of presenilin-1, presenilin-2, Aph1a, Aph1b, PEN-2, and nicastrin in a set of breast cancer tissue samples (N = 55) by quantitative real-time PCR in order to clarify the clinical significance of the expression of different γ-secretase complex components in breast cancer. We found a high positive correlation between the subunit expression levels implying a common regulation of transcription. Our univariate Kaplan-Meier survival analyses established low expression level of γ-secretase complex as a risk factor for breast cancer specific mortality. The tumors expressing low levels of γ-secretase complex were characterized by high histopathological tumor grade, low or no expression of estrogen and progesterone receptors and consequently high probability to fall into the class of triple negative breast cancer tumors. These results may provide novel tools to further categorize breast cancer tumors, especially the highly aggressive and poorly treatable breast cancer type of triple negative cases, and suggest a significant role for γ-secretase in breast cancer.

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Section: Discussioncontrasting

confidence: 61%

γ-Secretase Components as Predictors of Breast Cancer Outcome

et al. 2013

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“…Some subtle variations have been reported in the cellular distribution profile among the four γ-secretase subunits in selected brain regions as well as in certain peripheral tissues. For example, PEN-2 immunoreactivity, compared to other γ-secretase components, was found to be rather intense in mossy fiber terminal zone of the hippocampus [45], whereas nicastrin, but not PS1, was expressed at relatively high levels in the muscle membranes [21]. Whether these differences reflect unique functions of PEN-2 or nicastrin independent of the γ-secretase remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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“…However, previous studies showed that components of the γ‐secretase complex are not coordinately expressed in tissues. For example, NCT is highly expressed in muscle cells, whereas PSEN1 is very lowly expressed (Ilaya et al, ). These studies suggested that, in addition to forming the γ‐secretase complex, PSEN1 might also play independent roles in the maintenance of cardiac functions.…”

Section: Discussionmentioning

confidence: 99%

Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction

Song

Yuan

Tang

et al. 2017

Journal Cellular Physiology

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Recently, PSEN1 has been reported to have mutations in dilated cardiomyopathy pedigrees. However, the function and mechanism of PSEN1 in cardiomyopathy remains unresolved. Here, we established four types of genetically modified mice to determine the function of PSEN1 in cardiac development and pathology. PSEN1 null mutation resulted in perinatal death, retardation of heart growth, ventricular dilatation, septum defects, and valvular thickening. PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and reduced lengths of sarcomeres in cardiomyocytes. Cardiovascular loss of function of PSEN1 induced by Sm22a-Cre or Myh6-Cre/ER/tamoxifen also resulted in severe ultrastructural abnormalities, such as relaxed gap junctions between neighboring cardiomyocytes. Functionally, cardiovascular deletion of PSEN1 caused spontaneous mortality from birth to adulthood and led to diastolic heart dysfunction, including decreased volume of the left ventricle at the end-systolic and end-diastolic stages. Additionally, in a myocardial ischemia model, deletion of PSEN1 in the cardiovascular system first protected mice by inducing adaptive hypertrophy but ultimately resulted in severe heart failure. Furthermore, a collection of genes was abnormally expressed in the hearts of cardiac-specific PSEN1 knockout mice. They were enriched in cell proliferation, calcium regulation, and so on. Taken together, dynamic regulation and abnormal function of PSEN1 underlie the pathogenesis of cardiovascular diseases due to ultrastructural abnormality of cardiomyocytes.

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Nicastrin expression in mouse peripheral tissues is not co‐ordinated with presenilin and is high in muscle

Cited by 17 publications

References 52 publications

γ-Secretase Components as Predictors of Breast Cancer Outcome

γ-Secretase Components as Predictors of Breast Cancer Outcome

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction

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