HMGIC, the gene for an architectural transcription factor, is amplified and rearranged in a subset of human sarcomas

Berner, Jeanne Marie; Meza‐Zepeda, Leonardo A.; Kools, Patrick; Forus, Anne; Schoenmakers, Eric; Ven, Wim J.M. Van de; Fodstad, Øystein; Myklebost, Ola

doi:10.1038/sj.onc.1201135

Cited by 89 publications

(69 citation statements)

References 20 publications

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“…Most likely, the amplification of the locus containing MDM2 was selected for by overexpression of other genes, such as CDK4 or HMGA2. [32][33][34] Furthermore, contrary to common reports that TP53 Mut leads to accumulation of p53 protein, we found low p53 expression in these samples (Fig. 2).…”

Section: Discussioncontrasting

confidence: 99%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

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BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53 Wt ) tumors had improved survival (P < .001) and TP53 Wt was an independent prognostic factor (hazard ratio ¼ 0.41; 95% confidence interval ¼ 0.23-0.74; P ¼ .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P ¼ .07), which was strongest with doxorubicin/ifosfamide-based regimens (P ¼ .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53 Wt background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53 Wt tumors harboring the R72 variant. MDM2 overexpression in TP53 Wt tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to

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Section: Discussioncontrasting

confidence: 99%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

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“…The other major amplicon in sarcomas, 12q13-15, contain at least three candidate genes with a proposed role in tumour development, MDM2, HMGIC and CDK4 (Momand et al, 1992;Oliner et al, 1992;Forus et al, 1993;Khatib et al, 1993;Berner et al, 1996Berner et al, , 1997. The frequency of ampli®cation of the di erent genes may vary among di erent tumour types.…”

Section: Discussionmentioning

confidence: 99%

Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas–a possible mechanism for altering the nm23-H1 activity

et al. 2001

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PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly ampli®ed in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired a nity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found ampli®cation of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant ®brous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE ampli®cation was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE ampli®cation developed metastases. A similar situation was observed in all breast carcinomas with ampli®cation of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, ampli®-cation and overexpression of PRUNE has the same e ect in the tumours. We suggest that ampli®cation and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that a ect the development or progression of these tumours. Oncogene (2001) 20, 6881 ± 6890.

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“…Elevated levels of HMGI/Y in differentiated tissues have been found to be correlated with progressive and neoplastic transformations (27,28). Disruption or rearrangements of their genes lead to tumorigenesis (29,30).…”

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Protein Footprinting Reveals Specific Binding Modes of a High Mobility Group Protein I to DNAs of Different Conformation

Frank¹,

Schwanbeck²,

Wiśniewski

1998

Journal of Biological Chemistry

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The high mobility group proteins I and Y (HMGI/Y) are abundant components of chromatin. They are thought to derepress chromatin, affect the assembly and activity of the transcriptional machinery, and associate with constitutive heterochromatin during mitosis. HMGI/Y protein molecules contain three potential DNA-binding motifs (AT-hooks), but the extent of contacts between DNA and the entire protein has not been determined. We have used a protein-footprinting procedure to map regions of the Chironomus HMGI protein molecule that are involved in contacts with DNA. We find that in the presence of double-stranded DNA all AT-hook motifs are protected against hydroxyl radical proteolysis. In contrast, only two motifs were protected in the presence of four-way junction DNA. Large regions that flank the AT-hook motifs were found to be strongly protected against proteolysis in complexes with interferon-␤ promoter DNA, suggesting amino acid residues outside the AT-hooks considerably contribute to DNA binding.

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HMGIC, the gene for an architectural transcription factor, is amplified and rearranged in a subset of human sarcomas

Cited by 89 publications

References 20 publications

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas–a possible mechanism for altering the nm23-H1 activity

Protein Footprinting Reveals Specific Binding Modes of a High Mobility Group Protein I to DNAs of Different Conformation

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