<scp>CDK</scp>‐mediated activation of the <scp>SCF<sup>FBXO</sup></scp><sup>28</sup> ubiquitin ligase promotes <scp>MYC</scp>‐driven transcription and tumourigenesis and predicts poor survival in breast cancer

Cepeda, Diana; Ng, Hwee-Fang; Sharifi, H R; Mahmoudi, Salah; Soto‐Cerrato, Vanessa; Fredlund, Erik; Magnusson, Kristina; Nilsson, Helén; Malyukova, Alena; Rantala, Juha; Klevebring, Daniel; Viñals, Francesc; Bhaskaran, Nimesh; Zakaria, Siti Mariam; Rahmanto, Aldwin Suryo; Grotegut, Stefan; Nielsen, Michael L.; Szigyarto, Cristina Al‐Khalili; Sun, Dahui; Lerner, Mikael; Navani, Sanjay; Widschwendter, Martin; Uhlén, Mathias; Jirström, Karin; Pontén, Fredrik; Wohlschlegel, James A.; Grandér, Dan; Spruck, Charles; Larsson, Lars‐Gunnar; Sangfelt, Olle

doi:10.1002/emmm.201202341

Cited by 70 publications

(88 citation statements)

References 53 publications

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“…Hyperactivation of these CDKs promotes tumor development by initiating unscheduled cell division (9)(10)(11)(12)(13)(14)(15). It has also been documented that different CDKs may contribute specifically to different tumor types in humans (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…Since CDKs usually promote cell proliferation and often correlates with elevated expression levels in human tumors (9)(10)(11)(12)(13)(14)(15)(16)(17)(18), it is surprising to find that CDK5 levels are dramatically decreased in gastric cancers. This may suggest that CDK5 in fact plays an inhibitory role in gastric tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal expression and dysregulation of cyclins and CDKs have recently emerged as an important mechanism underlying the tumorigenesis of certain types of cancers (7,8). For example, dysregulation of classic CDKs including CDK1, CDK2, CDK3, CDK4, and CDK6 contributes to tumor development by initiating unscheduled cell division (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). However, detailed roles of CDKs in gastric tumorigenesis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cao

Zhou

Zhang

et al. 2015

Clinical Cancer Research

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Purpose: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown.Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and realtime PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth.Results: CDK5 level was significantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis.Conclusions: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cao

Zhou

Zhang

et al. 2015

Clinical Cancer Research

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“…Within SCF complexes, there resides a receptor component, the F-box protein, that engages substrates to facilitate their ubiquitylation. One F-box protein, Fbxo28 acts as an SCF subunit to mediate ubiquitin proteasomal degradation of Myc (Cepeda et al, 2013). Fbxo28 might also regulate cognitive function and impact the seizure phenotype observed in a rare microdeletion syndrome (Au et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

Zou

Synan

et al. 2016

Journal of Cell Science

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Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C 20 )-containing cardiolipin molecular species, whereas the content of C 18 or C 16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCFFbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity.

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“…4,5 However, the genes responsible for other phenotypes, in particular the brain morphological abnormalities, of the syndrome are unknown.…”

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confidence: 99%

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

et al. 2016

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Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

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CDK‐mediated activation of the SCF^FBXO²⁸ ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer

Cited by 70 publications

References 53 publications

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

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CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer

Cited by 70 publications

References 53 publications

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

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CDK‐mediated activation of the SCF^FBXO²⁸ ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer