HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity

Fedele, Monica; Visone, Rosa; Martino, Ivana De; Troncone, Giancarlo; Palmieri, Dario; Battista, Sabrina; Ciarmiello, Andrea; Pallante, Pierlorenzo; Arra, Claudio; Melillo, Rosa Marina; Helin, Kristian; Croce, Carlo M.; Fusco, Alfredo

doi:10.1016/j.ccr.2006.04.024

Cited by 230 publications

(235 citation statements)

References 23 publications

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“…For example, HMGA2 interacts with pRB to displace HDAC1, resulting in the enhanced activity of E2F1 (37). Our results herein propose an additional pathway, namely HMGA2-promoted PML protein degradation, underlying the oncogenic ability of HMGA2.…”

Section: Discussionmentioning

confidence: 63%

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Cao

Clavijo

et al. 2008

Molecular Cancer Therapeutics

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The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasomedependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation.Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2. [Mol Cancer Ther 2008;7(4):923-34]

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Section: Discussionmentioning

confidence: 63%

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Cao

Clavijo

et al. 2008

Molecular Cancer Therapeutics

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“…By binding to AT-rich DNA and interacting with histone-modifying enzymes and other proteins in enhanceosomes and chromatin, Hmga2 functions as a global epigenetic regulator (22,23). Using a dissociated prostate regeneration approach (24), we examined the contribution of Hmga2-modified stroma to prostate cancer initiation and progression and found that overexpression of stromal Hmga2 was extraordinarily potent and led to the development of multifocal PIN in a paracrine Wnt-dependent manner.…”

Section: Significancementioning

confidence: 99%

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Zong

Huang²,

Sankarasharma³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AThook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/β-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

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“…All the other transfections were performed by using Lipofectamine 2000 (Invitrogen), as suggested by the manufacturer. The pCEFL-HA-HMGA1, pCEFL-HA-HMGA2, pCEFL-HA-HMGA1 (1-43) and pCEFL-HA-HMGA2 (1-73) vectors were previously described (Fedele et al, 2006;Pierantoni et al, 2001;Pentimalli et al, 2008). The anti-HMGA1 antisense construct was described elsewhere (Berlingieri et al, 2002).…”

Section: Chemicals and Treatmentsmentioning

confidence: 99%

“…Antibodies used were anti-FLAG M2 (Sigma, St Louis, MO, USA), anti-HA Clone 12CA5 (Roche, Branford, CT, USA), anti-P-ATM-substrate (phospho-Ser/Thr antibody), anti-CHK2pThr68 (Cell Signalling Technology, Danvers, MA, USA), anti-ATM S1981p (Rockland, Philadelphia, PA, USA), anti-p53 DO-1, anti-p-p53 (Ser15), anti-ATM and anti-vinculin (7F9) (Santa Cruz, Santa Cruz, CA, USA). Anti-HMGA1 and anti-HMGA2 polyclonal antibodies were described elsewhere (Pierantoni et al, 2001;Fedele et al, 2006).…”

Section: Chemicals and Treatmentsmentioning

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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HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity

Cited by 230 publications

References 23 publications

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

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

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