High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity

Pierantoni, Giovanna Maria; Rinaldo, Cinzia; Esposito, Francesco; Mottolese, Marcella; Soddu, Silvia; Fusco, Alfredo

doi:10.1038/sj.cdd.4401839

Cited by 69 publications

(102 citation statements)

References 33 publications

(31 reference statements)

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“…Conversely Hmga1 KO MEFs did not show a reduction in the p53/p21 pathway, while Hmga2 KO MEFs displayed reduced levels of p21 mRNA and p53ser15 compared with wild-type MEFs. The absence of Hmga1-dependent inhibition of p53 (Pierantoni et al, 2006;Pierantoni et al, 2007) may account for this difference between Hmga1 and Hmga2 single knock-out MEFs. Our results also indicate a key role for HMGA proteins in the cellular DDR.…”

Section: Discussionmentioning

confidence: 99%

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxiatelangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage-and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.

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Section: Discussionmentioning

confidence: 99%

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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“…Electrophoretic mobility shift assay and supershift assay Electrophoretic mobility shift assay was performed as described earlier (Pierantoni et al, 2006). CREB consensus oligonucleotide probe was from Santa Cruz Biotechnology Inc (TransCruz Gel Shift Oligonucleotides).…”

Section: Transactivation Assaymentioning

confidence: 99%

“…ChIP and Re-ChIP assays After transfection, chromatin samples were processed for ChIP and Re-ChIP experiments as reported elsewhere (Pierantoni et al, 2006). Samples were subjected to immunoprecipitation with the following specific antibodies: anti-CCDC6 (Celetti et al, 2004), anti-CREB1, anti-HDAC1(06720), anti-acetylHistone-H3, (Upstate Biotecnology); anti-PP1 (Santa Cruz Biotechnology Inc.).…”

Section: Transactivation Assaymentioning

confidence: 99%

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

et al. 2010

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RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.

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“…Recently, HMGA1-p53 interactions have been demonstrated to affect carcinogenesis. HMGA1 binds with p53, thus interfering with the p53-mediated transcription of BCL2-associated X protein (BAX), P21Waf1, MDM2 and B-Cell CLL/Lymphoma 2 (BCL2); this results in reduced p53-dependent apoptosis (29)(30)(31). HMGA1 also inhibits p53 apoptotic function by relocalizing the nuclear p53 proapoptotic activator Homeodomain-interacting protein kinase 2 (HIPK2) to the cytoplasm (32).…”

Section: Introductionmentioning

confidence: 99%

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

Lin¹,

Peng²

2015

Oncology Letters

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Abstract. The roles of Silent mating type information regulation 2 homolog 1 (SIRT1) and High mobility group A1 (HMGA1) in human diseases have been extensively studied separately; however, to the best of our knowledge, the current study is the first to report on their interrelationship in lung cancer. The association of SIRT1 and HMGA1 in non-small cell lung cancer (NSCLC) was investigated by evaluating their expression and prognostic significance in 260 patients with NSCLC using immunohistochemistry. SIRT1 and HMGA1 expression were found to be significantly correlated with each other (P<0.001), and both were significantly associated with clinicopathological parameters, including histological type and degree of differentiation. In squamous cell carcinoma (SCC), SIRT1 + specimens were significantly associated with shorter overall survival (OS) time (P=0.019). However, in patients with adenocarcinoma (AD), no association was identified between SIRT1 and OS. In addition, HMGA1 + specimens were significantly associated with poor differentiation (P=0.028), and were more frequent in SCC than AD (P=0.015). However, HMGA1 was not associated with OS on univariate Cox regression analysis or Kaplan-Meier analysis (both P>0.05). SIRT1/HMGA1 coexpression was significantly associated with male gender (P=0.016), and moderately and poorly differentiated histological grade (P=0.025). The findings indicate that SIRT1 and HMGA1 may have significant effects during tumor progression in NSCLC, particularly in patients with SCC, and are potentially useful as prognostic indicators for patients with NSCLC.

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High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity

Cited by 69 publications

References 33 publications

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

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