The RelA/p65 subunit of NF‐κB specifically regulates cyclin D1 protein stability: Implications for cell cycle withdrawal and skeletal myogenesis

Dahlman, Jason M.; Wang, David J.; Bakkar, Nadine; Guttridge, Denis C.

doi:10.1002/jcb.21976

Cited by 31 publications

(18 citation statements)

References 56 publications

(107 reference statements)

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“…NF-κB induces the expression of a number of oncogenes involved in the regulation of multiple cellular process including cell proliferation and survival [34, 35]. Moreover, emerging evidence suggests that NF-κB is constitutively active in PC [36, 37]; however, the exact molecular mechanism(s) responsible for the activation of NF-κB in PC is not well understood.…”

Section: Discussionmentioning

confidence: 99%

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

et al. 2014

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Identification of novel molecular targets and understanding the mechanisms underlying the aggressive nature of pancreatic cancer (PC) remain prime focus areas of research. Here, we investigated the expression and pathobiological significance of p21-activated kinase 4 (PAK4), a gene that was earlier shown to be amplified in a sub-set of PC. Our data demonstrate PAK4 overexpression in PC tissues and cell lines with little or no expression in the normal pancreas. PAK4 silencing in two PC cell lines, MiaPaCa and T3M4, by RNA interference causes suppression of growth and clonogenic ability due to decreased cell cycle progression and apoptosis-resistance. PAK4-silenced PC cells exhibit altered expression of proliferation- and survival-associated proteins. Moreover, we observe decreased nuclear accumulation and transcriptional activity of NF-κB in PAK4-silenced PC cells associated with stabilization of its inhibitory protein, IκBα. Transfection of PAK4-silenced PC cells with constitutively-active mutant of IKKβ, an upstream kinase of IκBα, leads to restoration of NF-κB activity and PC cell growth. Furthermore, we show that PAK4-induced NF-κB activity is mediated through activation and concerted action of ERK and Akt kinases. Together, these findings suggest that PAK4 is a regulator of NF-κB pathway in PC cells and can serve as a novel target for therapy.

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Section: Discussionmentioning

confidence: 99%

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

et al. 2014

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“…Cyclin 1)1, itself a reported repressor of myogenesis (140), is also a transcriptional target of NF-kB (53). The cyclin 1)1 protein was also recently reported to interact and be stabilized by p65 (37). Furthermore, classical NF-kB sub units can suppress the synthesis of MyoD by acting through a destabilization element in the MyoD transcript in response to TNF-a and TWEAK signaling (42,54,139).…”

Section: Nf-kb Inhibits Myogenesis Through Multiple Mechanismsmentioning

confidence: 93%

NF-κB Signaling: A Tale of Two Pathways in Skeletal Myogenesis

Bakkar

Guttridge

2010

Physiological Reviews

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171

157

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NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

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“…It is unclear whether NF-B is a promyogenic or an anti-myogenic factor during muscle differentiation as relevant data are conflicting, but suppression of myogenesis by means of inhibiting MyoD, myogenin and myofibrillar gene expression has been linked to canonical NF-B signaling [244][245][246][247][248][249][250][251][252]. In contrast, noncanonical NF-B signaling that involves IKK and RelB does not affect myogenesis but drives an oxidative muscle fiber switch by targeting PGC-1 which stimulates mitochondrial biogenesis [253].…”

Section: Inflammatory Pathways In Skeletal Musclementioning

confidence: 99%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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(150 -250 words) [165] Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferatoractivated receptor  coactivators 1 (PGC-1) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-B) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

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The RelA/p65 subunit of NF‐κB specifically regulates cyclin D1 protein stability: Implications for cell cycle withdrawal and skeletal myogenesis

Cited by 31 publications

References 56 publications

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

NF-κB Signaling: A Tale of Two Pathways in Skeletal Myogenesis

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

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