Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway

Upadhyay, Mamta; Gupta, Smriti; Bhadauriya, Pratibha; Ganesh, Subramaniam

doi:10.1016/j.bbrc.2015.06.018

Cited by 8 publications

(4 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Animals at four different age groups (Postnatal day 21 [P21], 3 months old, 6 months old, and 1 year old) were used for the study. Genotyping of animals was done, as reported earlier (Upadhyay, Agarwal, Bhadauriya, & Ganesh, 2017; Upadhyay, Gupta, Bhadauriya, & Ganesh, 2015).…”

Section: Methodsmentioning

confidence: 99%

Dendritic spine abnormalities correlate with behavioral and cognitive deficits in mouse models of Lafora disease

Taneja

Ganesh

2020

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

Lafora disease (LD) is a genetic and fatal form of neurodegenerative disorder characterized by myoclonic epilepsy and cognitive deficits. LD is caused by loss‐of‐function mutations in the EPM2A or the NHLRC1 gene. A major hallmark of LD is the presence of abnormal glycogen aggregates in neurons and other tissues. Functional studies on the genes have, therefore, mostly focused on glycogen metabolism. The physiological basis of cognitive deficits in LD is thus largely unexplored. Alterations in dendritic spine morphology are known in neurodevelopmental and neuropsychiatric disorders. We, therefore, analyzed the dendritic spine morphologies in pyramidal neurons of the hippocampal and Cortical layer V of the Epm2a or Nhlrc1 knockout mice brain. We found a significant increase in the density, length, and reduction in the width of the dendritic spines in Postnatal day 21 to 12‐month‐old LD animals. Similar observations were made in the primary cultures of neurons derived from the hippocampi of the embryonic brain, suggesting that the aberrant spine phenotype could be a developmental defect in LD. We also looked at the cognitive and behavioral deficits as a possible readout of the spine abnormalities. The LD animals exhibited hyperactivity, reduced anxiety‐like behavior, and deficits in the spatial and nonspatial memory. Such abnormalities were seen in the younger (1–2 months) as well as the older (7–8 months) age groups. Taken together, our results suggest that the dendritic spine abnormalities are primary developmental defects in the LD model and these defects might underlie some of the symptoms, including cognitive deficits, in LD.

show abstract

Section: Methodsmentioning

confidence: 99%

Dendritic spine abnormalities correlate with behavioral and cognitive deficits in mouse models of Lafora disease

Taneja

Ganesh

2020

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…NHLRC1 was previously functionally characterized only in Lafora disease, a neurodegenerative type of myoclonus epilepsy [38,39]. Its cellular functions include the regulation of the mTOR pathway, microRNA processing body formation, glucose metabolism and autophagy [24,40,41]. However, these findings were linked to loss of function mutations in NHLRC1 in the context of Lafora disease.…”

Section: Discussionmentioning

confidence: 99%

“…NHLRC1 was reported to contribute to p53 inactivation through nuclear to cytoplasmic translocation of homeodomain-interacting protein kinase-2 (HIPK2). Thus, elevated NHLRC1 expression in lung tumor tissue may be a mechanism to inhibit TP53-pathway regulated induction of apoptosis in lung cancer [41]. The tripartite motif containing 32 (TRIM32), another RING-type ubiquitin E3 ligase and structurally highly similar to NHLRC1 was shown to be deregulated in several malignancies leading to direct TP53 proteasomal degradation [42][43][44][45].…”

Section: Discussionmentioning

confidence: 99%

Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS)

Faltus

Lahnsteiner

Barrdahl

et al. 2022

IJMS

View full text Add to dashboard Cite

Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region of NHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest gene NHLRC1 in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion upon NHLRC1 knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data. NHLRC1 holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.

show abstract

“…In particular, NBR1 is involved in ensuring ubiquitinated protein degradation, whose inappropriate aggregation is a common feature to numerous neurodegenerative and neuromuscular diseases (Nicot et al, 2014). HIPK2 has been involved in several neurodegenerative diseases, such as Parkinson, Alzheimer, and Lafora disease, mainly because of its role in proapoptotic induction (Lanni et al, 2010;Upadhyay et al, 2015). The HIPK2 role in autophagy regulation opens a scenario in which this kinase might function in the control of cell death and of protein aggregation.…”

Section: Figure 4 | Continuedmentioning

confidence: 99%

HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation

Sardina

Monteonofrio

Ferrara

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

At the end of abscission, the residual midbody forms the so-called midbody remnant (MBR), a platform affecting cell fate with emerging key role in differentiation, development, and tumorigenicity. Depending on cell type and pathophysiological context, MBRs undergo different outcomes: they can be retained, released, internalized by nearby cells, or removed through autophagy-mediated degradation. Although mechanisms underlying MBR formation, positioning, and processing have been recently identified, their regulation is still largely unknown. Here, we report that the multifunctional kinase HIPK2 regulates MBR processing contributing to MBR removal. In the process of studying the role of HIPK2 in abscission, we observed that, in addition to cytokinesis failure, HIPK2 depletion leads to significant accumulation of MBRs. In particular, we detected comparable accumulation of MBRs after HIPK2 depletion or treatment with the autophagic inhibitor chloroquine. In contrast, single depletion of the two independent HIPK2 abscission targets, extrachromosomal histone H2B and severing enzyme Spastin, only marginally increased MBR retention, suggesting that MBR accumulation is not just linked to cytokinesis failure. We found that HIPK2 depletion leads to (i) increased levels of CEP55, a key effector of both midbody formation and MBR degradation; (ii) decreased levels of the selective autophagy receptors NBR1 and p62/SQSTM1; and (iii) impaired autophagic flux. These data suggest that HIPK2 contributes to MBR processing by regulating its autophagy-mediated degradation.

show abstract

Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway

Cited by 8 publications

References 36 publications

Dendritic spine abnormalities correlate with behavioral and cognitive deficits in mouse models of Lafora disease

Dendritic spine abnormalities correlate with behavioral and cognitive deficits in mouse models of Lafora disease

Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS)

HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation

Contact Info

Product

Resources

About