<i>Hmga1</i>null mouse embryonic fibroblasts display downregulation of spindle assembly checkpoint gene expression associated to nuclear and karyotypic abnormalities

Pierantoni, Giovanna Maria; Conte, Andrea; Rinaldo, Cinzia; Tornincasa, Mara; Gerlini, Raffaele; Valente, Davide; Izzo, Antonella

doi:10.1080/15384101.2016.1146835

Cited by 9 publications

(9 citation statements)

References 27 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 1 , 2 , 3 , 4 , 5 , 6 , 7 HMGA proteins contribute to carcinogenesis by several mechanisms: (a) inactivation of p53-induced apoptosis 28 and regulation of cancer stem cell division; 29 (b) impairment of DNA repair; 3 (c) transcriptional regulation of miRNAs and genes involved in the control of the cell cycle 30 , 31 and induction of epithelial-mesenchymal transition; 32 , 33 (d) induction of AP-1 activity; 34 (e) induction of chromosome instability. 35 , 36 Nevertheless, it is general opinion that HMGA1 exerts its oncogenic activity also by other unidentified mechanisms.…”

Section: Discussionmentioning

confidence: 99%

High mobility group A1 protein modulates autophagy in cancer cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

High Mobility Group A1 (HMGA1) is an architectural chromatin protein whose overexpression is a feature of malignant neoplasias with a causal role in cancer initiation and progression. HMGA1 promotes tumor growth by several mechanisms, including increase of cell proliferation and survival, impairment of DNA repair and induction of chromosome instability. Autophagy is a self-degradative process that, by providing energy sources and removing damaged organelles and misfolded proteins, allows cell survival under stress conditions. On the other hand, hyper-activated autophagy can lead to non-apoptotic programmed cell death. Autophagy deregulation is a common feature of cancer cells in which has a complex role, showing either an oncogenic or tumor suppressor activity, depending on cellular context and tumor stage. Here, we report that depletion of HMGA1 perturbs autophagy by different mechanisms. HMGA1-knockdown increases autophagosome formation by constraining the activity of the mTOR pathway, a major regulator of autophagy, and transcriptionally upregulating the autophagy-initiating kinase Unc-51-like kinase 1 (ULK1). Consistently, functional experiments demonstrate that HMGA1 binds ULK1 promoter region and negatively regulates its transcription. On the other hand, the increase in autophagosomes is not associated to a proportionate increase in their maturation. Overall, the effects of HMGA1 depletion on autophagy are associated to a decrease in cell proliferation and ultimately impact on cancer cells viability. Importantly, silencing of ULK1 prevents the effects of HMGA1-knockdown on cellular proliferation, viability and autophagic activity, highlighting how these effects are, at least in part, mediated by ULK1. Interestingly, this phenomenon is not restricted to skin cancer cells, as similar results have been observed also in HeLa cells silenced for HMGA1. Taken together, these results clearly indicate HMGA1 as a key regulator of the autophagic pathway in cancer cells, thus suggesting a novel mechanism through which HMGA1 can contribute to cancer progression.

show abstract

Section: Discussionmentioning

confidence: 99%

High mobility group A1 protein modulates autophagy in cancer cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…HMGA proteins have a well-established oncogenic activity, and usually their expression correlates with a highly malignant phenotype 12 . HMGA1 controls a wide spectrum of cell functions, including cell proliferation and survival 17 , genomic stability 18,19 , and autophagy 20 . During development, HMGA proteins are involved also in the regulation of body size, as demonstrated by the observation of the “superpygmy” phenotype of the Hmga1 / Hmga2 double knock-out (DKO) mice 21 .…”

Section: Introductionmentioning

confidence: 99%

Double knock-out of Hmga1 and Hipk2 genes causes perinatal death associated to respiratory distress and thyroid abnormalities in mice

et al. 2019

Self Cite

View full text Add to dashboard Cite

The serine–threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.

show abstract

“…The lysates were incubated for 30 min on ice, and supernatants were collected and centrifuged for 10 min at 14,000× g . Protein concentration was estimated by a modified Bradford assay and 25 or 50 μg/lane of total proteins were separated on SDS gels and transferred to nitrocellulose membranes [ 66 ]. Membranes were treated with a blocking buffer (25 mM Tris, pH 7.4, 200 mM NaCl, 0.5% Triton X-100) containing 5% non-fat powdered milk for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Convergent Effects of Resveratrol and PYK2 on Prostate Cells

Conte

Kisslinger

Procaccini

et al. 2016

IJMS

Self Cite

View full text Add to dashboard Cite

Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.

show abstract

Hmga1null mouse embryonic fibroblasts display downregulation of spindle assembly checkpoint gene expression associated to nuclear and karyotypic abnormalities

Cited by 9 publications

References 27 publications

High mobility group A1 protein modulates autophagy in cancer cells

High mobility group A1 protein modulates autophagy in cancer cells

Double knock-out of Hmga1 and Hipk2 genes causes perinatal death associated to respiratory distress and thyroid abnormalities in mice

Convergent Effects of Resveratrol and PYK2 on Prostate Cells

Contact Info

Product

Resources

About