Sp1 and Sp3 regulate transcription of the cyclin-dependent kinase 5 regulatory subunit 2 (p39) promoter in neuronal cells

Valín, Álvaro; Cook, Julie D.; Ross, Sarah E.; Saklad, Christi L.; Gill, Grace

doi:10.1016/j.bbagrm.2009.01.007

Cited by 16 publications

(15 citation statements)

References 42 publications

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“…4). Furthermore, earlier reports by Valin et al, showed the importance of repeated GC box elements that bind Sp1, Sp3 and Sp4 in-vitro , to direct neuron-specific expression of the cdk5 regulator p35 (Valin et al, 2009). Thus, these posttranslational regulators of tau may also be subject to the same epigenetic reprogramming and transcriptional machinery that also impacts tau gene expression, culminating in not only an elevation of total tau but also in the enzymes involved in its phosphorylation (Bihaqi et al, 2012).…”

Section: Discussionmentioning

confidence: 96%

Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb)

Bihaqi

2013

NeuroToxicology

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Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (~90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aβ) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development.

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Section: Discussionmentioning

confidence: 96%

Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb)

Bihaqi

2013

NeuroToxicology

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“…Cdk5/p39 is also responsible for Munc18-1 phosphorylation during Ca ++ -induced insulin exocytosis [31] and phosphorylates the microtubule protein tau in the developing mouse brain [31]. The in vivo specificity of Cdk5/p39 versus Cdk5/p35 may be controlled by spatial and temporal regulation of their expression [32, 33] or by specific subcellular localization mediated by particular binding partners of p35 and p39 [34]. …”

Section: Discussionmentioning

confidence: 99%

The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens

Tripathi

Lowy

Zelenka

2015

Experimental Cell Research

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Cyclin dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, requires p39 for its enzymatic activity, and is implicated in cytoskeletal organization and contraction in numerous cell types. The C-terminus of p39 binds muskelin, a multi-domain scaffolding protein known to affect cytoskeletal organization, but the mechanism(s) by which muskelin affects cytoskeletal organization remain unclear. The present study sought to determine whether p39 might serve as an adaptor protein that links muskelin to stress fibers and to investigate the possible biological relevance of such an interaction. Double immunoprecipitation showed that muskelin, p39, and myosin II are components of a single intracellular complex, and suppressing p39 abrogated the interaction between muskelin and the myosin subunits, demonstrating that p39 is required to link muskelin to myosin II. Muskelin is colocalized with myosin regulatory light chain (MRLC) and on stress fibers. The suppression of muskelin reduced Rho-GTP, MRLC phosphorylation, disrupted stress fiber organization, and promoted cell migration, all of which closely mimics the effect of Cdk5 inhibition. Moreover, suppressing muskelin and inhibiting Cdk5 together has no additional effect, indicating that muskelin plays an important role in Cdk5-dependent signaling. P39 is necessary and sufficient for Cdk5-dependent regulation of MRLC phosphorylation, as suppression of p39, but not p35, reduced MRLC phosphorylation. Together, these results demonstrate that p39 specifically links muskelin to myosin II and consequently, to stress fibers and reveal a novel role for muskelin in regulating myosin phosphorylation and cytoskeletal organization.

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“…The in silico prediction analysis showed that FTO‐ risk variants could have a direct effect on modulating binding sites of transcription factors such as SP1 , SP2 and FOXP1 during brain development, which suggests a possible effect of these transcription factors on a FTO ‐risk variant dependent on brain development mechanism. Supporting these data, in animal models it has been described that alterations in expression levels of these transcription factors ( SP1 , SP2 and FOXP1 ) have a direct effect reducing the morphogenesis of the brain (Li et al., ; Valin, Cook, Ross, Saklad, & Gill, ). Binding sites of SP1 and SP2 were predicted to be disturbed by BD‐associated variants, and are transcription factors that play critical roles in embryonic and early development (Safe, Imanirad, Sreevalsan, Nair, & Jutooru, ).…”

Section: Discussionmentioning

confidence: 83%

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

et al. 2019

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Introduction Several studies indicate that polygenic obesity is linked to fat‐mass and obesity‐associated ( FTO ) genetic variants. Nevertheless, the link between variants in FTO and mental disorders has been barely explored. The present work aims to determine whether FTO genetic variants are associated with bipolar disorder and obesity, and to perform an in silico prediction of variant‐dependent functional impact on the developing brain transcriptome. Methods Four hundred and forty‐six Mexican mestizos were included in a genetic association analysis. SNP ‐sequence kernel association test and linear mixed models were implemented for genetic association assessment. For functional impact prediction, we analyzed the mapping of regulatory elements, the modification of binding sites of transcription factors and the expression of transcription factors in the brain developing transcriptome, searching on different databases. Results In the set‐based analysis, we found different associated regions to BD (bipolar disorder) and obesity. The promoter flanking region of FTO intron 1 was associated with differential effects on BMI , while intron 2 of RPGRIP 1L and FTO upstream regions were associated with BD . The prediction analysis showed that FTO BD ‐associated variants disturb binding sites of SP 1 and SP 2; obesity‐associated variants, on the other hand, disturb binding sites of FOXP 1, which are transcription factors highly expressed during prenatal development stages of the brain. Conclusion Our results suggest a possible effect of FTO variants on neurodevelopment in obesity and bipolar disorder, which gives new insights into the molecular mechanism underlying this association.

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Sp1 and Sp3 regulate transcription of the cyclin-dependent kinase 5 regulatory subunit 2 (p39) promoter in neuronal cells

Cited by 16 publications

References 42 publications

Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb)

Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb)

The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

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