SP3 and AP‐1 mediate transcriptional activation of the lamin A proximal promoter

Muralikrishna, Bh; Parnaik, Veena K.

doi:10.1046/j.1432-1327.2001.02281.x

Cited by 13 publications

(10 citation statements)

References 40 publications

(73 reference statements)

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“…Possibly, Akt exerts this control through regulation of effectors such as FoxO, Sp1/Sp3, AP1, and CREB. Indeed, binding‐domain‐specific transcription factors, such as SP1/3 or AP1, have been reported in prelamin A promoter (50, 51). However, we cannot exclude the possibility that Akt modulates prelamin A expression through an indirect mechanism, and this aspect deserves deeper investigation.…”

Section: Discussionmentioning

confidence: 99%

The protein kinase Akt/PKB regulates both prelamin A degradation and Lmna gene expression

et al. 2013

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The serine/threonine kinase Akt/PKB is a major signaling hub integrating metabolic, survival, growth, and cell cycle regulatory signals. The definition of the phospho-motif cipher driving phosphorylation by Akt led to the identification of hundreds of putative substrates, and it is therefore pivotal to identify those whose phosphorylation by Akt is of consequence to biological processes. The Lmna gene products lamin A/C and the lamin A precursor prelamin A are type V intermediate filament proteins forming a filamentous meshwork, the lamina, underneath the inner nuclear membrane, for nuclear envelope structures organization and interphase chromatin anchoring. In our previous work, we reported that A-type lamins are phosphorylated by Akt at S301 and S404 in physiological conditions and are therefore bona fide substrates of Akt. We report here that Akt phosphorylation at S404 targets the precursor prelamin A for degradation. We further demonstrate that Akt also regulates Lmna transcription. Our study unveils a previously unknown function of Akt in the control of prelamin A stability and expression. Moreover, given the large number of diseases related to prelamin A, our findings represent a further important step bridging basic A-type lamin physiology to therapeutic approaches for lamin A-linked disorders.

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Section: Discussionmentioning

confidence: 99%

The protein kinase Akt/PKB regulates both prelamin A degradation and Lmna gene expression

et al. 2013

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“…Post-translational modifications and interactions with other factors have been shown to regulate Sp1 DNA binding and transcriptional activity (50,52,(63)(64)(65). The transcriptional properties of Sp3 are complex (44,54,66), as Sp3 can function as either a transcriptional activator (67)(68)(69) or a repressor (56, 70 -73). Interestingly, whether Sp3 functions as an activator or a repressor depends on promoter architecture (54,66,73).…”

Section: Discussionmentioning

confidence: 99%

GC Box-binding Transcription Factors Control the Neuronal Specific Transcription of the Cyclin-dependent Kinase 5 Regulator p35

Ross¹,

Tienhaara²,

Lee³

et al. 2002

Journal of Biological Chemistry

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Cyclin-dependent kinase 5 (cdk5)/p35 kinase activity is highest in post-mitotic neurons of the central nervous system and is critical for development and function of the brain. The neuronal specific activity of the cdk5/p35 kinase is achieved through the regulated expression of p35 mRNA. We have identified a small 200-bp fragment of the p35 promoter that is sufficient for high levels of neuronal specific expression. Mutational analysis of this TATA-less promoter has identified a 17-bp GC-rich element, present twice, that is both required for promoter activity and sufficient for neuronal specific transcription. A GC box within the 17-bp element is critical for both promoter activity and protein-DNA complex formation. The related transcription factors Sp1, Sp3, and Sp4 constitute most of the GC box DNA binding activity in neurons. We have found that both the relative contribution of the Sp family proteins to GC box binding and the transcriptional activity of these proteins is regulated during neuronal differentiation. Thus, our data show that the GC box-binding Sp proteins contribute to the regulation of p35 expression in neurons, suggesting changes in the Sp transcription factors level and activity may contribute to cell type-specific expression of many genes in the central nervous system.The DNA elements and transcription factors regulating the spatial and temporal expression of genes in the central nervous system are critical for its development and function. Cyclin-dependent kinase 5 (cdk5) 1 has kinase activity that is primarily detected in the brain, although cdk5 itself has a broader distribution (1, 2). The neuronal specificity of cdk5 kinase activity is achieved through its association with an obligate regulatory partner, either p35 (3-5) or p39 (6, 7), whose expression patterns are spatially and temporally regulated (8 -13). p35 expression is predominant in the brain (4, 5) and is highest in post-mitotic neurons of the central nervous system, with expression peaking in actively migrating cells in the developing cerebral cortex (11, 13). The p35 protein has a short half-life (14), and during embryogenesis there is a direct correlation between p35 mRNA levels and cdk5 kinase activity (11, 13), suggesting that regulation of p35 mRNA levels is the major determinant controlling cdk5 activity during development.The proper regulation of cdk5 kinase activity is essential for development and maintenance of the central nervous system. A gene disruption of either cdk5 or p35 leads to an abnormal development of the brain, and the cdk5 disruption is lethal (15, 16). The most striking brain abnormality resulting from disruption of the p35 gene is a severe cortical lamination defect characterized by the reversed packing order of cortical neurons, suggesting that the cdk5/p35 kinase is important for neuronal migration. Dominant negative cdk5 mutants as well as antisense p35 have been found to inhibit neurite outgrowth, supporting a role for cdk5/p35 kinase in this process during neuronal differentiation (17-19). Identif...

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“…In contrast, A-type lamin expression is developmentally regulated. Some of the transcriptional regulators that control the promoter activity of the LMNA gene include AP1 (activating protein 1), Sp1/3 (Muralikrishna & Parnaik, 2001), hepatocyte nuclear factor-3 β , retinoic X receptor β (Arora et al 2004) and p53 (Rahman-Roblick et al 2007). Although A-type lamins are initially present in fertilized oocytes, they are absent during early embryonic development and become expressed in a tissue-specific manner during the middle stages of embryonic development as well as during postnatal development (Stewart & Burke 1987;Broers et al 1997).…”

Section: A-type Lamins As Defenders Against Growthrelated Postnatal Smentioning

confidence: 99%

Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches

Pekovic

Hutchison

2008

Journal of Anatomy

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Adult stem cells have been identified in most mammalian tissues of the adult body and are known to support the continuous repair and regeneration of tissues. A generalized decline in tissue regenerative responses associated with age is believed to result from a depletion and/or a loss of function of adult stem cells, which itself may be a driving cause of many age-related disease pathologies. Here we review the striking similarities between tissue phenotypes seen in many degenerative conditions associated with old age and those reported in age-related nuclear envelope disorders caused by mutations in the LMNA gene. The concept is beginning to emerge that nuclear filament proteins, A-type lamins, may act as signalling receptors in the nucleus required for receiving and/ or transducing upstream cytosolic signals in a number of pathways central to adult stem cell maintenance as well as adaptive responses to stress. We propose that during ageing and in diseases caused by lamin A mutations, dysfunction of the A-type lamin stress-resistant signalling network in adult stem cells, their progenitors and/or stem cell niches leads to a loss of protection against growth-related stress. This in turn triggers an inappropriate activation or a complete failure of self-renewal pathways with the consequent initiation of stress-induced senescence. As such, A-type lamins should be regarded as intrinsic modulators of ageing within adult stem cells and their niches that are essential for survival to old age.

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SP3 and AP‐1 mediate transcriptional activation of the lamin A proximal promoter

Cited by 13 publications

References 40 publications

The protein kinase Akt/PKB regulates both prelamin A degradation and Lmna gene expression

The protein kinase Akt/PKB regulates both prelamin A degradation and Lmna gene expression

GC Box-binding Transcription Factors Control the Neuronal Specific Transcription of the Cyclin-dependent Kinase 5 Regulator p35

Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches

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