High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas

Deshmukh, Hrishikesh; Yeh, Tu Hsueh; Yu, Jinsheng; Sharma, Mukesh Kumar; Perry, Arie; Leonard, Jeffrey R.; Watson, Mark A.; Gutmann, David H.; Nagarajan, Rakesh

doi:10.1038/onc.2008.110

Cited by 96 publications

(85 citation statements)

References 34 publications

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“…Pfister et al (2008) identified duplication of 7q34 within 139186224 -140156951 in 30 of 66 (45.5%) paediatric LGA. This region included BRAF, a gene which was not in the genetic interval described in Deshmukh et al (2008). The authors confirmed the absence of previously described BRAF oncogenic mutations in their sample set, and showed that silencing of BRAF in a LGA cell line decreased cell proliferation rates.…”

supporting

confidence: 70%

“…Recently several consecutive papers described duplication of 7q34 in LGA including JPA (Bar et al, 2008;Deshmukh et al, 2008;Jones et al, 2008;Pfister et al, 2008;Sievert et al, 2008). However, the data reported are conflicting regarding the subgroup of LGA affected by this genetic event, the size of the duplication and its anatomical localisation within the brain.…”

mentioning

confidence: 86%

“…However, the data reported are conflicting regarding the subgroup of LGA affected by this genetic event, the size of the duplication and its anatomical localisation within the brain. Indeed, Deshmukh et al (2008) identified amplification of 7q34 in 8 of 10 cerebellar JPA at 138151200 -139456000, which included HIPK2, a potential gene of interest. The authors further showed using an immunohistochemical approach that overexpression of HIPK2 was more frequent in LGA than in high-grade gliomas, and that it was more common in infratentorial tumours.…”

mentioning

confidence: 99%

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Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

et al. 2009

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BACKGROUND: Juvenile pilocytic astrocytomas (JPA), a subgroup of low-grade astrocytomas (LGA), are common, heterogeneous and poorly understood subset of brain tumours in children. Chromosomal 7q34 duplication leading to fusion genes formed between KIAA1549 and BRAF and subsequent constitutive activation of BRAF was recently identified in a proportion of LGA, and may be involved in their pathogenesis. Our aim was to investigate additional chromosomal unbalances in LGA and whether incidence of 7q34 duplication is associated with tumour type or location. METHODS AND RESULTS: Using Illumina-Human-Hap300-Duo and 610-Quad high-resolution-SNP-based arrays and quantitative PCR on genes of interest, we investigated 84 paediatric LGA. We demonstrate that 7q34 duplication is specific to sporadic JPA (35 of 53 -66%) and does not occur in other LGA subtypes (0 of 27) or NF1-associated-JPA (0 of 4). We also establish that it is site specific as it occurs in the majority of cerebellar JPA (24 of 30 -80%) followed by brainstem, hypothalamic/optic pathway JPA (10 of 16 -62.5%) and is rare in hemispheric JPA (1 of 7 -14%). The MAP-kinase pathway, assessed through ERK phosphorylation, was active in all tumours regardless of 7q34 duplication. Gain of function studies performed on hTERT-immortalised astrocytes show that overexpression of wild-type BRAF does not increase cell proliferation or baseline MAPK signalling even if it sensitises cells to EGFR stimulation. CONCLUSIONS AND INTERPRETATION: Our results suggest that variants of JPA might arise from a unique site-restricted progenitor cell where 7q34 duplication, a hallmark of this tumour-type in association to MAPK-kinase pathway activation, potentially plays a sitespecific role in their pathogenesis. Importantly, gain of function abnormalities in components of MAP-Kinase signalling are potentially present in all JPA making this tumour amenable to therapeutic targeting of this pathway.

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confidence: 70%

mentioning

confidence: 86%

mentioning

confidence: 99%

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Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

et al. 2009

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“…In pilocytic astrocytoma, HIPK2 gene is frequently amplified (40-60%) and HIPK2 overexpression stimulates cell growth (Deshmukh et al, 2008). Strong HIPK2 immunostaining in cervical cancer tissues was also hypothesized to correlate with tumor progression (Al-Beiti and Lu, 2008).…”

Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 99%

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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The p53 protein is the most studied tumor suppressor and the p53 pathway has been shown to mediate cellular stress responses that are disrupted when cancer develops. After DNA damage, p53 is activated as transcription factor to directly induce the expression of target genes involved in cell-cycle arrest, DNA repair, senescence and, importantly, apoptosis. Post-translational modifications of p53 are essential for the activation of p53 and for selection of target genes. The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating its N-terminal serine 46 (Ser46) and facilitating Lys382 acetylation at the C-terminus. HIPK2 is activated by numerous genotoxic agents and can be deregulated in tumors by several conditions including hypoxia. Recent findings suggest that HIPK2 active/inactive protein can affect p53 function in multiple and unexpected ways. This makes p53 as well as HIPK2 interesting targets for cancer therapy. Hence, understanding the role of HIPK2 as p53 activator may provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer.

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“…HIPK2 is overexpressed in some brain tumors (Deshmukh et al, 2008). It would be interesting to determine whether ZBTB4 is downregulated at the protein level in these same tumors, and whether this contributes to their malignancy by a mechanism involving p21.…”

Section: Hipk2 Phosphorylates and Downregulates Zbtb4mentioning

confidence: 99%

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

et al. 2009

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HIPK2 is a eukaryotic Serine-Threonine kinase that controls cellular proliferation and survival in response to exogenous signals. Here, we show that the human transcription factor ZBTB4 is a new target of HIPK2. The two proteins interact in vitro, colocalize and associate in vivo, and HIPK2 phosphorylates several conserved residues of ZBTB4. Overexpressing HIPK2 causes the degradation of ZBTB4, whereas overexpressing a kinasedeficient mutant of HIPK2 has no effect. The chemical activation of HIPK2 also decreases the amount of ZBTB4 in cells. Conversely, the inhibition of HIPK2 by drugs or by RNA interference causes a large increase in ZBTB4 levels. This negative regulation of ZBTB4 by HIPK2 occurs under normal conditions of cell growth. In addition, the degradation is increased by DNA damage. These findings have two consequences. First, we have recently shown that ZBTB4 inhibits the transcription of p21. Therefore, the activation of p21 by HIPK2 is twopronged: stimulation of the activator p53, and simultaneous repression of the inhibitor ZBTB4. Second, ZBTB4 is also known to bind methylated DNA and repress methylated sequences. Consequently, our findings raise the possibility that HIPK2 might influence the epigenetic regulation of gene expression at loci that remain to be identified.

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High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas

Cited by 96 publications

References 34 publications

Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

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