1,721,036 research outputs found
Cell-penetrating peptides: two faces of the same coin
No full textCell-penetrating peptides (CPPs) are short peptides able to cross the cellular membranes without any interaction with specific receptors. Thanks to their ability to transport various cargo inside the cells are emerged as powerful therapeutic agents alternative to small molecules. In recent years, numerous preclinical studies provided promising results for the treatment of various human diseases. Several CPP-conjugated compounds are under clinical trials
Regulation of HIPK Proteins by MicroRNAs
No full textThe homeodomain-interacting protein kinase (HIPK) family consists of four evolutionarily conserved and highly related nuclear serine/threonine kinases of recent discovery. They interact with homeobox proteins and other transcription factors, as well as transcriptional coactivators or corepressors depending on the cellular context. HIPK proteins are sensors for various extracellular stimuli, which control key cellular functions such as signal transduction to downstream effectors that regulate apoptosis, embryonic development, DNA-damage response, and cellular proliferation. Thus, HIPKs are involved in proliferative diseases such as cancer and fibrosis. mRNA levels and protein stability tightly regulate expression levels of HIPKs
Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs
No full textThe homeodomain-interacting protein kinases (HIPKs) HIPK1, HIPK2 and HIPK3 are
Ser/Thr kinases which interact with homeobox proteins and other transcription factors, acting as transcriptional
coactivators or corepressors. HIPKs contribute to regulate several biological processes,
such as signal transduction, apoptosis, embryonic development, DNA-damage response, and cellular
proliferation, in response to various extracellular stimuli. Recently it has emerged that, in addition to
their role in cancer, fibrosis and diabetes, HIPKs may also be involved in other human diseases, including
amyotrophic lateral sclerosis (ALS), Rett syndrome, cerebellar diseases, and retinal vascular
dysfunction.
Methods: Here, we update our previous paper concerning the regulation of HIPK proteins expression
by microRNAs (miRNAs), pointing out the most recent findings about new cellular mechanisms and
diseases which are affected by the interplay between HIPKs and miRNAs.
Conclusion: Recently, it has emerged that HIPKs and their related miRNAs are involved in diabetic
nephropathy, gastric cancer chemoresistance, cervical cancer progression, and recombinant protein
expression in cultured cells. Interestingly, circular RNAs (circRNAs) deriving from HIPK2 and
HIPK3 loci also modulate cellular proliferation and viability by sponging several miRNAs, thus
emerging as new putative therapeutic targets for diabetes-associated retinal vascular dysfunction,
astrogliosis and cancer
Critical role of the HMGA2 gene in pituitary adenomas.
No full textThe molecular pathway leading to pituitary tumorigenesis is still largely unknown and is one of the challenges of the endocrine oncology. The development of pituitary adenomas in HMGA2 transgenic mice and the finding of HMGA2 amplification and overexpression in human pituitary adenomas led us to investigate the mechanism by which the HMGA2 gene plays a crucial role in pituitary oncogenesis. This mechanism has been recently described by our group: it entails the acetylation of E2F1, and its consequent enhanced activity, following the displacement of HDAC1 from the pRB/E2F1 inhibitory complex. Based on the mating between HMGA2 transgenic and E2F1 knockout mice, the activation of E2F1 appears to be the main mechanism of the onset of HMGA2-induced pituitary adenoma development. Nevertheless, other events may be also involved in this process, and are discussed here
HIPK2 in cancer biology and therapy: Recent findings and future perspectives
Full text linkHomeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates and regulates a plethora of transcriptional regulators and chromatin modifiers. The heterogeneity of its interactome allows HIPK2 to modulate several cellular processes and signaling pathways, ultimately regulating cell fate and proliferation. Because of its p53-dependent pro-apoptotic activity and its downregulation in many tumor types, HIPK2 is traditionally considered a bone fide tumor suppressor gene. However, recent findings revealed that the role of HIPK2 in the pathogenesis of cancer is much more complex, ranging from tumor suppressive to oncogenic, strongly depending on the cellular context. Here, we review the very recent data emerged in the last years about the involvement of HIPK2 in cancer biology and therapy, highlighting the various alterations of this kinase (downregulation, upregulation, mutations and/or delocalization) in dependence on the cancer types. In addition, we discuss the recent advancement in the understanding the tumor suppressive and oncogenic functions of HIPK2, its role in establishing the response to cancer therapies, and its regulation by cancer-associated microRNAs. All these data strengthen the idea that HIPK2 is a key player in many types of cancer; therefore, it could represent an important prognostic marker, a factor to predict therapy response, and even a therapeutic target itself
High mobility group A-interacting proteins in cancer: focus on chromobox protein homolog 7, homeodomain interactin protein kinase 2 and PATZ
Full text linkDown-Regulation of the miR-25 and miR-30d Contributes to the Development of Anaplastic Thyroid Carcinoma Targeting the Polycomb Protein EZH2.
No full textContext:We have previously demonstrated that a set of micro-RNA (miRNA) is significantly down-regulated in anaplastic thyroid carcinomas with respect to normal thyroid tissues and to differentiated thyroid carcinomas.Objective:The objective was to evaluate the role of two of these down-regulated miRNA, miR-25 and miR-30d, in thyroid carcinogenesis.Design:miR-25 and miR-30d expression was restored in the ACT-1, 8505c, and FRO anaplastic thyroid cell lines, and their effects on cell proliferation, migration, and target expression were evaluated.Results:We report that miR-25 and miR-30d target the polycomb protein enhancer of zeste 2 (EZH2) that has oncogenic activity and is drastically up-regulated in anaplastic thyroid carcinomas but not in the differentiated ones. Ectopic expression of miR-25 and miR-30d inhibited proliferation and colony formation of anaplastic thyroid carcinoma cells by inducing G2/M-phase cell-cycle arrest. Finally, we found an inverse correlation between the expression of these miRNA and the EZH2 protein levels in anaplastic thyroid carcinomas, suggesting a critical role of these miRNA in regulating EZH2 expression also in vivo.Conclusion:The down-regulation of miR-25 and miR-30d could contribute to the process of thyroid cancer progression, leading to the development of anaplastic carcinomas targeting EZH2 mRNA
PATZ1 interacts with p53 and regulates expression of p53-target genes enhancing apoptosis or cell survival based on the cellular context.
No full textPATZ1 is a transcriptional factor functioning either as an activator or a repressor of gene transcription depending upon the cellular context. It appears to have a dual oncogenic/anti-oncogenic activity. Indeed, it is overexpressed in colon carcinomas, and its silencing inhibits colon cancer cell proliferation or increases sensitivity to apoptotic stimuli of glioma cells, suggesting an oncogenic role. Conversely, the development of B-cell lymphomas, sarcomas, hepatocellular carcinomas and lung adenomas in Patz1-knockout (ko) mice supports its tumour suppressor function. PATZ1 role in mouse lymphomagenesis is mainly because of the involvement of PATZ1 in BCL6-negative autoregulation. However, this does not exclude that PATZ1 may be involved in tumorigenesis by other mechanisms. Here, we report that PATZ1 interacts with the tumour suppressor p53 and binds p53-dependent gene promoters, including those of BAX, CDKN1A and MDM2. Knockdown of PATZ1 in HEK293 cells reduces promoter activity of these genes and inhibits their expression, suggesting a role of PATZ in enhancing p53 transcriptional activity. Consistently, Patz1-ko mouse embryonic fibroblasts (MEFs) show decreased expression of Bax, Cdkn1a and Mdm2 compared with wild-type (wt) MEFs. Moreover, Patz1-ko MEFs show a decreased percentage of apoptotic cells, either spontaneous or induced by treatment with 5-fluorouracil (5FU), compared with wt controls, suggesting a pro-apoptotic role for PATZ1 in these cells. However, PATZ1 binds p53-target genes also independently from p53, exerting, in the absence of p53, an opposite function on their expression. Indeed, knockdown of PATZ1 in p53-null osteosarcoma cells upregulates BAX expression and decreases survival of 5FU-treated cells, then suggesting an anti-apoptotic role of PATZ1 in p53-null cancer cells. Therefore, these data support a PATZ1 tumour-suppressive function based on its ability to enhance p53-dependent transcription and apoptosis. Conversely, its opposite and anti-apoptotic role in p53-null cancer cells provides the perspective of PATZ1 silencing as a possible adjuvant in the treatment of p53-null cancer
Pax8 has a critical role in epithelial cell survival and proliferation
No full textThe transcription factor Pax8, a member of the Paired-box gene family, is a critical regulator required for proper development and
differentiation of thyroid follicular cells. Despite being Pax8 well characterized with respect to its role in regulating genes
responsible for thyroid differentiation, its involvement in cell survival and proliferation has been hypothesized but remains
unclear. Here, we show that Pax8 overexpression significantly increases proliferation and colony-forming efficiency of Fischer
rat thyroid line 5 epithelial cells, although it is not sufficient to overcome their hormone dependence. More interestingly, we show
that Pax8-specific silencing induces apoptosis through a p53-dependent pathway that involves caspase-3 activation and
cleavage of poly(ADP)ribose polymerase. Our data indicate that tumor protein 53 induced nuclear protein 1 (tp53inp1), a positive
regulator of p53-dependent cell cycle arrest and apoptosis, is a transcriptional target of Pax8 and is upregulated by Pax8
knockdown. Remarkably, tp53inp1 silencing significantly abolishes Pax8-induced apoptosis thus suggesting that tp53inp1 may
be the mediator of the observed effects. In conclusion, our data highlight that Pax8 is required for the survival of differentiated
epithelial cells and its expression levels are able to modulate the proliferation rate of such cells
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