Treatment of metastatic disease remains among the most challenging tasks in oncology. One of the ... more Treatment of metastatic disease remains among the most challenging tasks in oncology. One of the early events that predicts a poor prognosis and precedes the development of metastasis is the occurrence of clusters of cancer cells in the blood flow. Moreover, the presence of heterogeneous clusters of cancerous and noncancerous cells in the circulation is even more dangerous. Review of pathological mechanisms and biological molecules directly involved in the formation and pathogenesis of the heterotypic circulating tumor cell (CTC) clusters revealed their common properties, which include increased adhesiveness, combined epithelial-mesenchymal phenotype, CTC-white blood cell interaction, and polyploidy. Several molecules involved in the heterotypic CTC interactions and their metastatic properties, including IL6R, CXCR4 and EPCAM, are targets of approved or experimental anticancer drugs. Accordingly, analysis of patient survival data from the published literature and public datasets rev...
<p><b>A.</b> Scatterplott of changes in RNAP binding after differentiation vers... more <p><b>A.</b> Scatterplott of changes in RNAP binding after differentiation versus RNAP binding in undifferentiated keratinocytes show 797 and 841 promoters are induced or repressed upon differentiation. These changes correlate with changes in mRNA levels. <b>B.</b> Transcription factors CREB, C/EBPβ and c-Jun bind distinct set of promoters in differentiated keratinocytes. Euler diagrams show that promoters bound by C/EBPβ and c-Jun are preferentially induced by differentiation and promoters bond by CREB are not. <b>C.</b> Fraction of promoters bound by different combination of transcription factors in differentiated keratinocytes where RNAP binding is repressed (white bars) or induced by differentiation (black bars). <b>D.</b> Fraction of genes with mRNA levels induced or repressed by differentiation more than 1.4 times in groups of promoters bound by different combinations of transcription factors. * - values are different from expected (p<0.005 using a two-tailed unpaired t-test).</p
<p><b>A.</b> Transcription factor binding distributions in all promoters, promo... more <p><b>A.</b> Transcription factor binding distributions in all promoters, promoters bound by CREB, C/EBPβ and c-Jun, and promoters bound by all three of these proteins that are also either induced or repressed upon differentiation. Columns show the mean value of the binding affinity for each of the three transcription factors in these four groups of promoters, while error bars show the 15% and 85% percentiles. The binding affinity of CREB is significantly lower in promoters bound by all three transcription factors and induced by differentiation. Number on top represents the p-value from an unpaired t-test. <b>B.</b> Chip-PCR for promoter regions of SPRP1A and DNAse1L3 induced by differentiation. CREB binding is low in comparison with C/EBPβ and c-Jun. 3′ GAPDH region was not enriched in these samples.</p
<p><b>A.</b> Top DNA motifs mostly enriched in test sets v.s. background sets o... more <p><b>A.</b> Top DNA motifs mostly enriched in test sets v.s. background sets of promoters in the −500 bp…0 bp relative to the transcription start site. Motifs are sorted by enrichment and statistical confidence level using CisFinder. For CREB, c-Jun C/EBPβ set cJun and C/EBPβ bound promoters were used as a background. <b>B.</b> Enrichment of promoters containing only two or three transcription factors consensus binding motifs in groups of promoters bound by different combination of transcription factors in undifferentiated keratinocytes. Consensus motifs for CREB (CRE) - TGACGTCA, C/EBPβ - (C/EBP) TTGCGCAA and for c-Jun (AP-1) TGA(C/G)TCA. Note that promoters containing combination of motifs are overrepresented in the groups of promoters bound by corresponding transcription factor. * - numbers are different from expected (p<0.05).</p
Lung malignancies accounted for 11% of cancers worldwide in 2020 and remained the leading cause o... more Lung malignancies accounted for 11% of cancers worldwide in 2020 and remained the leading cause of cancer deaths. About 80% of lung cancers belong to non-small cell lung cancer (NSCLC), which is characterized by extremely high clonal and morphological heterogeneity of tumors and development of multidrug resistance. The improvement of current therapeutic strategies includes several directions. First, increasing knowledge in cancer biology results in better understanding of the mechanisms underlying malignant transformation, alterations in signal transduction, and crosstalk between cancer cells and the tumor microenvironment, including immune cells. In turn, it leads to the discovery of important molecular targets in cancer development, which might be affected pharmaceutically. The second direction focuses on the screening of novel drug candidates, synthetic or from natural sources. Finally, “personalization” of a therapeutic strategy enables maximal damage to the tumor of a patient. ...
Metal ion homeostasis is fundamental for life. Specifically, transition metals iron, manganese an... more Metal ion homeostasis is fundamental for life. Specifically, transition metals iron, manganese and zinc play a pivotal role in mitochondrial metabolism and energy generation, anti-oxidation defense, transcriptional regulation and the immune response. The misregulation of expression or mutations in ion carriers and the corresponding changes in Mn2+ and Zn2+ levels suggest that these ions play a pivotal role in cancer progression. Moreover, coordinated changes in Mn2+ and Zn2+ ion carriers have been detected, suggesting that particular mechanisms influenced by both ions might be required for the growth of cancer cells, metastasis and immune evasion. Here, we present a review of zinc and manganese pathophysiology suggesting that these ions might cooperatively regulate cancerogenesis. Zn and Mn effects converge on mitochondria-induced apoptosis, transcriptional regulation and the cGAS-STING signaling pathway, mediating the immune response. Both Zn and Mn influence cancer progression and...
Epidemiologic studies show a positive association between obesity and cancer risk. In addition to... more Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-...
<p><b>A.</b> Euler diagrams of methylated and unmethylated promoters bound by d... more <p><b>A.</b> Euler diagrams of methylated and unmethylated promoters bound by different combination of transcription factors show that CREB binding is depleted on methylated promoters while C/EBPβ and c-Jun binding is overrepresented. <b>B.</b> Percent of promoters with RNAP is induced or repressed by differentiation in promoters bound by different combinations of transcription factors in differentiated keratinocytes for unmethylated (left) and methylated promoters (right). <b>C.</b> Percent of genes with mRNA is induced or repressed by differentiation in promoters bound by different combinations of transcription factors in differentiated keratinocytes for unmethylated (left) and methylated promoters (right). * - numbers are significantly different from expected, (p<0.05).</p
We used a double transgenic tetracycline system to conditionally express A-CREB, a dominant negat... more We used a double transgenic tetracycline system to conditionally express A-CREB, a dominant negative protein that prevents the DNA binding and function of cAMP-responsive element binding protein (CREB) family members, in mouse basal epidermis using the keratin 5 promoter. There was no phenotype in the adult. However, following a 7,12-dimethylbenz(a)anthracene (DMBA)/phorbol-12-myristate-13-acetate two-stage skin carcinogenesis experiment, A-CREB–expressing epidermis develop 5-fold fewer papillomas than wild-type controls. However, A-CREB expression one month after DMBA treatment does not prevent papilloma formation, suggesting that CREB functions at an early stage of papilloma formation. Oncogenic H-Ras genes with A→T mutations in codon 61 were found in wild-type skin but not in A-CREB–expressing skin 2 days after DMBA treatment, suggesting that A-CREB either prevents DMBA mutagenesis or kills oncogenic H-Ras cells. In primary keratinocyte cultures, A-CREB expression induced apoptos...
Understanding the mechanisms that regulate cancer progression is pivotal for the development of n... more Understanding the mechanisms that regulate cancer progression is pivotal for the development of new therapies. Although p53 is mutated in half of human cancers, its family member p73 is not. At the same time, isoforms of p73 are often overexpressed in cancers and p73 can overtake many p53 functions to kill abnormal cells. According to the latest studies, while p73 represses epithelial–mesenchymal transition and metastasis, it can also promote tumour growth by modulating crosstalk between cancer and immune cells in the tumor microenvironment, M2 macrophage polarisation, Th2 T-cell differentiation, and angiogenesis. Thus, p73 likely plays a dual role as a tumor suppressor by regulating apoptosis in response to genotoxic stress or as an oncoprotein by promoting the immunosuppressive environment and immune cell differentiation.
Research article All and only CpG containing sequences are enriched in promoters abundantly bound... more Research article All and only CpG containing sequences are enriched in promoters abundantly bound by RNA polymerase II in multiple tissues
Background: Transcription factors CREB, C/EBPb and Jun regulate genes involved in keratinocyte pr... more Background: Transcription factors CREB, C/EBPb and Jun regulate genes involved in keratinocyte proliferation and differentiation. We questioned if specific combinations of CREB, C/EBPb and c-Jun bound to promoters correlate with RNA polymerase II binding, mRNA transcript levels and methylation of promoters in proliferating and differentiating keratinocytes. Results: Induction of mRNA and RNA polymerase II by differentiation is highest when promoters are bound by C/EBP b alone, C/EBPb together with c-Jun, or by CREB, C/EBPb and c-Jun, although in this case CREB binds with low affinity. In contrast, RNA polymerase II binding and mRNA levels change the least upon differentiation when promoters are bound by CREB either alone or in combination with C/EBPb or c-Jun. Notably, promoters bound by CREB have relatively high levels of RNA polymerase II binding irrespective of differentiation. Inhibition of C/EBPb or c-Jun preferentially represses mRNA when gene promoters are bound by correspond...
Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in n... more Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in nanomedicine. Typically, this strategy involves the addition of cancer-targeting biomolecules to nanoparticles, and studies on this topic have mainly focused on the localization of such formulations in tumors. Here, the analysis of the factors determining efficient nanoparticle targeting and therapy, various parameters such as types of targeting molecules, nanoparticle type, size, zeta potential, dose, and the circulation time are given. In addition, the important aspects such as how active targeting of nanoparticles alters biodistribution and how non-specific organ uptake influences tumor accumulation of the targeted nanoformulations are discussed. The analysis reveals that an increase in tumor accumulation of targeted nanoparticles is accompanied by a decrease in their uptake by the spleen. There is no association between targeting-induced changes of nanoparticle concentrations in tumor...
BACKGROUND In normal human blood, RBC volume (V), surface area (A) and hemoglobin content (H) exh... more BACKGROUND In normal human blood, RBC volume (V), surface area (A) and hemoglobin content (H) exhibit Gaussian distributions with coefficients of variation (CV) of 10-15%. Strikingly narrower distributions are observed for their cell density (CV approximately 0.5%) and filterability (CV approximately 5-7%). This implies that V is highly correlated with H and A. We hypothesize that the RBC is able to adjust its volume to parameters H and A. It is tempting to speculate that intracellular free calcium (Cai) is a mediator in this process, acting as an activator of the Gardos channel. We tested this hypothesis by experimentally varying Cai and measuring changes in RBC density and filterability distributions. MATERIAL/METHODS Three different approaches were used to raise Cai: (i) RBCs were loaded with Ca2+ in the presence of the calcium ionophore A23187; (ii) RBCs were incubated with Ca2+ in the presence of 1.0 mM ortho-vanadate; and (iii) the calcium pump was switched off by ATP depletio...
During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeost... more During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanism...
Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the... more Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.
Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the... more Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.
Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the... more Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.
Treatment of metastatic disease remains among the most challenging tasks in oncology. One of the ... more Treatment of metastatic disease remains among the most challenging tasks in oncology. One of the early events that predicts a poor prognosis and precedes the development of metastasis is the occurrence of clusters of cancer cells in the blood flow. Moreover, the presence of heterogeneous clusters of cancerous and noncancerous cells in the circulation is even more dangerous. Review of pathological mechanisms and biological molecules directly involved in the formation and pathogenesis of the heterotypic circulating tumor cell (CTC) clusters revealed their common properties, which include increased adhesiveness, combined epithelial-mesenchymal phenotype, CTC-white blood cell interaction, and polyploidy. Several molecules involved in the heterotypic CTC interactions and their metastatic properties, including IL6R, CXCR4 and EPCAM, are targets of approved or experimental anticancer drugs. Accordingly, analysis of patient survival data from the published literature and public datasets rev...
<p><b>A.</b> Scatterplott of changes in RNAP binding after differentiation vers... more <p><b>A.</b> Scatterplott of changes in RNAP binding after differentiation versus RNAP binding in undifferentiated keratinocytes show 797 and 841 promoters are induced or repressed upon differentiation. These changes correlate with changes in mRNA levels. <b>B.</b> Transcription factors CREB, C/EBPβ and c-Jun bind distinct set of promoters in differentiated keratinocytes. Euler diagrams show that promoters bound by C/EBPβ and c-Jun are preferentially induced by differentiation and promoters bond by CREB are not. <b>C.</b> Fraction of promoters bound by different combination of transcription factors in differentiated keratinocytes where RNAP binding is repressed (white bars) or induced by differentiation (black bars). <b>D.</b> Fraction of genes with mRNA levels induced or repressed by differentiation more than 1.4 times in groups of promoters bound by different combinations of transcription factors. * - values are different from expected (p<0.005 using a two-tailed unpaired t-test).</p
<p><b>A.</b> Transcription factor binding distributions in all promoters, promo... more <p><b>A.</b> Transcription factor binding distributions in all promoters, promoters bound by CREB, C/EBPβ and c-Jun, and promoters bound by all three of these proteins that are also either induced or repressed upon differentiation. Columns show the mean value of the binding affinity for each of the three transcription factors in these four groups of promoters, while error bars show the 15% and 85% percentiles. The binding affinity of CREB is significantly lower in promoters bound by all three transcription factors and induced by differentiation. Number on top represents the p-value from an unpaired t-test. <b>B.</b> Chip-PCR for promoter regions of SPRP1A and DNAse1L3 induced by differentiation. CREB binding is low in comparison with C/EBPβ and c-Jun. 3′ GAPDH region was not enriched in these samples.</p
<p><b>A.</b> Top DNA motifs mostly enriched in test sets v.s. background sets o... more <p><b>A.</b> Top DNA motifs mostly enriched in test sets v.s. background sets of promoters in the −500 bp…0 bp relative to the transcription start site. Motifs are sorted by enrichment and statistical confidence level using CisFinder. For CREB, c-Jun C/EBPβ set cJun and C/EBPβ bound promoters were used as a background. <b>B.</b> Enrichment of promoters containing only two or three transcription factors consensus binding motifs in groups of promoters bound by different combination of transcription factors in undifferentiated keratinocytes. Consensus motifs for CREB (CRE) - TGACGTCA, C/EBPβ - (C/EBP) TTGCGCAA and for c-Jun (AP-1) TGA(C/G)TCA. Note that promoters containing combination of motifs are overrepresented in the groups of promoters bound by corresponding transcription factor. * - numbers are different from expected (p<0.05).</p
Lung malignancies accounted for 11% of cancers worldwide in 2020 and remained the leading cause o... more Lung malignancies accounted for 11% of cancers worldwide in 2020 and remained the leading cause of cancer deaths. About 80% of lung cancers belong to non-small cell lung cancer (NSCLC), which is characterized by extremely high clonal and morphological heterogeneity of tumors and development of multidrug resistance. The improvement of current therapeutic strategies includes several directions. First, increasing knowledge in cancer biology results in better understanding of the mechanisms underlying malignant transformation, alterations in signal transduction, and crosstalk between cancer cells and the tumor microenvironment, including immune cells. In turn, it leads to the discovery of important molecular targets in cancer development, which might be affected pharmaceutically. The second direction focuses on the screening of novel drug candidates, synthetic or from natural sources. Finally, “personalization” of a therapeutic strategy enables maximal damage to the tumor of a patient. ...
Metal ion homeostasis is fundamental for life. Specifically, transition metals iron, manganese an... more Metal ion homeostasis is fundamental for life. Specifically, transition metals iron, manganese and zinc play a pivotal role in mitochondrial metabolism and energy generation, anti-oxidation defense, transcriptional regulation and the immune response. The misregulation of expression or mutations in ion carriers and the corresponding changes in Mn2+ and Zn2+ levels suggest that these ions play a pivotal role in cancer progression. Moreover, coordinated changes in Mn2+ and Zn2+ ion carriers have been detected, suggesting that particular mechanisms influenced by both ions might be required for the growth of cancer cells, metastasis and immune evasion. Here, we present a review of zinc and manganese pathophysiology suggesting that these ions might cooperatively regulate cancerogenesis. Zn and Mn effects converge on mitochondria-induced apoptosis, transcriptional regulation and the cGAS-STING signaling pathway, mediating the immune response. Both Zn and Mn influence cancer progression and...
Epidemiologic studies show a positive association between obesity and cancer risk. In addition to... more Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-...
<p><b>A.</b> Euler diagrams of methylated and unmethylated promoters bound by d... more <p><b>A.</b> Euler diagrams of methylated and unmethylated promoters bound by different combination of transcription factors show that CREB binding is depleted on methylated promoters while C/EBPβ and c-Jun binding is overrepresented. <b>B.</b> Percent of promoters with RNAP is induced or repressed by differentiation in promoters bound by different combinations of transcription factors in differentiated keratinocytes for unmethylated (left) and methylated promoters (right). <b>C.</b> Percent of genes with mRNA is induced or repressed by differentiation in promoters bound by different combinations of transcription factors in differentiated keratinocytes for unmethylated (left) and methylated promoters (right). * - numbers are significantly different from expected, (p<0.05).</p
We used a double transgenic tetracycline system to conditionally express A-CREB, a dominant negat... more We used a double transgenic tetracycline system to conditionally express A-CREB, a dominant negative protein that prevents the DNA binding and function of cAMP-responsive element binding protein (CREB) family members, in mouse basal epidermis using the keratin 5 promoter. There was no phenotype in the adult. However, following a 7,12-dimethylbenz(a)anthracene (DMBA)/phorbol-12-myristate-13-acetate two-stage skin carcinogenesis experiment, A-CREB–expressing epidermis develop 5-fold fewer papillomas than wild-type controls. However, A-CREB expression one month after DMBA treatment does not prevent papilloma formation, suggesting that CREB functions at an early stage of papilloma formation. Oncogenic H-Ras genes with A→T mutations in codon 61 were found in wild-type skin but not in A-CREB–expressing skin 2 days after DMBA treatment, suggesting that A-CREB either prevents DMBA mutagenesis or kills oncogenic H-Ras cells. In primary keratinocyte cultures, A-CREB expression induced apoptos...
Understanding the mechanisms that regulate cancer progression is pivotal for the development of n... more Understanding the mechanisms that regulate cancer progression is pivotal for the development of new therapies. Although p53 is mutated in half of human cancers, its family member p73 is not. At the same time, isoforms of p73 are often overexpressed in cancers and p73 can overtake many p53 functions to kill abnormal cells. According to the latest studies, while p73 represses epithelial–mesenchymal transition and metastasis, it can also promote tumour growth by modulating crosstalk between cancer and immune cells in the tumor microenvironment, M2 macrophage polarisation, Th2 T-cell differentiation, and angiogenesis. Thus, p73 likely plays a dual role as a tumor suppressor by regulating apoptosis in response to genotoxic stress or as an oncoprotein by promoting the immunosuppressive environment and immune cell differentiation.
Research article All and only CpG containing sequences are enriched in promoters abundantly bound... more Research article All and only CpG containing sequences are enriched in promoters abundantly bound by RNA polymerase II in multiple tissues
Background: Transcription factors CREB, C/EBPb and Jun regulate genes involved in keratinocyte pr... more Background: Transcription factors CREB, C/EBPb and Jun regulate genes involved in keratinocyte proliferation and differentiation. We questioned if specific combinations of CREB, C/EBPb and c-Jun bound to promoters correlate with RNA polymerase II binding, mRNA transcript levels and methylation of promoters in proliferating and differentiating keratinocytes. Results: Induction of mRNA and RNA polymerase II by differentiation is highest when promoters are bound by C/EBP b alone, C/EBPb together with c-Jun, or by CREB, C/EBPb and c-Jun, although in this case CREB binds with low affinity. In contrast, RNA polymerase II binding and mRNA levels change the least upon differentiation when promoters are bound by CREB either alone or in combination with C/EBPb or c-Jun. Notably, promoters bound by CREB have relatively high levels of RNA polymerase II binding irrespective of differentiation. Inhibition of C/EBPb or c-Jun preferentially represses mRNA when gene promoters are bound by correspond...
Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in n... more Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in nanomedicine. Typically, this strategy involves the addition of cancer-targeting biomolecules to nanoparticles, and studies on this topic have mainly focused on the localization of such formulations in tumors. Here, the analysis of the factors determining efficient nanoparticle targeting and therapy, various parameters such as types of targeting molecules, nanoparticle type, size, zeta potential, dose, and the circulation time are given. In addition, the important aspects such as how active targeting of nanoparticles alters biodistribution and how non-specific organ uptake influences tumor accumulation of the targeted nanoformulations are discussed. The analysis reveals that an increase in tumor accumulation of targeted nanoparticles is accompanied by a decrease in their uptake by the spleen. There is no association between targeting-induced changes of nanoparticle concentrations in tumor...
BACKGROUND In normal human blood, RBC volume (V), surface area (A) and hemoglobin content (H) exh... more BACKGROUND In normal human blood, RBC volume (V), surface area (A) and hemoglobin content (H) exhibit Gaussian distributions with coefficients of variation (CV) of 10-15%. Strikingly narrower distributions are observed for their cell density (CV approximately 0.5%) and filterability (CV approximately 5-7%). This implies that V is highly correlated with H and A. We hypothesize that the RBC is able to adjust its volume to parameters H and A. It is tempting to speculate that intracellular free calcium (Cai) is a mediator in this process, acting as an activator of the Gardos channel. We tested this hypothesis by experimentally varying Cai and measuring changes in RBC density and filterability distributions. MATERIAL/METHODS Three different approaches were used to raise Cai: (i) RBCs were loaded with Ca2+ in the presence of the calcium ionophore A23187; (ii) RBCs were incubated with Ca2+ in the presence of 1.0 mM ortho-vanadate; and (iii) the calcium pump was switched off by ATP depletio...
During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeost... more During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanism...
Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the... more Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.
Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the... more Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.
Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the... more Epithelial organs are the first barrier against microorganisms and genotoxic stress, in which the p53 family members p63 and p73 have both overlapping and distinct functions. Intriguingly, p73 displays a very specific localization to basal epithelial cells in human tissues, while p63 is expressed in both basal and differentiated cells. Here, we analyse systematically the literature describing p63 and p73 protein–protein interactions to reveal distinct functions underlying the aforementioned distribution. We have found that p73 and p63 cooperate in the genome stability surveillance in proliferating cells; p73 specific interactors contribute to the transcriptional repression, anaphase promoting complex and spindle assembly checkpoint, whereas p63 specific interactors play roles in the regulation of mRNA processing and splicing in both proliferating and differentiated cells. Our analysis reveals the diversification of the RNA and DNA specific functions within the p53 family.
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Papers by Julian M Rozenberg