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Functional Analysis of the HOX11 Target Genes ALDH1A1 and FHL1Kim.Rice@mssm.edu, Kim Lee Rice January 2004 (has links)
HOX11 is a developmental regulator that plays a crucial role in the normal development
of the spleen and is also aberrantly activated by the t(10;14)(q24;q11) and variant
t(7;10)(q35;q24) translocations in a subset of T-cell acute lymphoblastic leukaemias (TALLs).
The recent finding that HOX11 is deregulated in up to 40% of childhood TALLs
when abnormalities not detected by cytogenetics are included, suggests that the
over-expression of HOX11 and subsequent deregulation of downstream target genes are
critical events in the progression of this tumour type. To date, three candidate HOX11
target genes have been reported, two of which are Aldehyde Dehydrogenase 1a1
(ALDH1A1) and Four and a Half LIM domain Protein 1 (FHL1). This investigation
focused on two aspects of HOX11 function, namely its roles as a transcriptional
regulator and as a nuclear oncoprotein capable of inducing neoplastic transformation.
More specifically, we sought to further understand the role of HOX11 in tumorigenesis
by 1) Confirming target gene status of ALDH1A1 and FHL1 by assessing whether their
proximal promoter regions are transcriptionally regulated by HOX11, 2) Investigating
the regulatory elements/transcriptional complexes involved in the response of
ALDH1A1 to HOX11 in both a T-cell and an erythroid cell line in order to gain an
insight into the mechanism(s) responsible for mediating a HOX11 activity and 3)
Assessing the ability of ALDH1A1 and FHL1 to perturb normal patterns of
haematopoiesis, on the basis that the transforming capabilities of HOX11 are thought to
derive from its ability to affect haematopoietic cell differentiation.
To confirm ALDH1A1 and FHL1 as target genes, they were both characterised in terms
of the ability of their proximal promoters to be transcriptionally regulated by HOX11
using luciferase reporter assays. Significant repression of the proximal promoters of
ALDH1A1 and FHL1 by HOX11 was observed in PER-117 T-cells which provided
further evidence for their status as target genes. In the case of ALDH1A1, a CCAAT box
(-74/-70bp) was identified as the primary cis-regulatory element involved in ALDH1A1
transcription and repression by HOX11 appeared to occur, either directly or indirectly,
via interactions at the CCAAT box. Electromobility shift assays (EMSAs) revealed the
disruption of a specific complex at this site by HOX11, which also altered the formation
of complexes at a non-canonical TATA box (a GATA box at -34/-29bp). Significantly,
HOX11 was shown to have the potential to interact with TFIIB, a member of the basal
transcriptional complex. This, together with the presence of a TFIIB responsive element
immediately 5 of the GATA box, suggested that HOX11 may repress transcription by
interfering with members of a preinitiation complex on the ALDH1A1 promoter. The
transcriptional repression by HOX11 demonstrated in T-cells was dependent on DNA
binding helix 3 of the homeodomain, suggesting that repression may require DNA
binding. Alternatively, this region may be required for stable protein-protein
interactions. In support of this, the in vitro association of HOX11 with TFIIB was
disrupted upon deletion of helix 3, and the HOX11∆H3 mutant switched from a
transcriptional repressor to a potent activator of transcription. Together, this data
supports a model whereby HOX11 represses transcription by interfering with activation
complexes at the CCAAT box and at the GATA box possibly via protein-protein
interactions involving the homeodomain helix 3, whereas deletion of the region disables
repressor-specific interactions, resulting in potent activation by HOX11.
Luciferase reporter gene assays investigating the response of nested deletions of the
ALDH1A1 promoter to HOX11 in the HEL900 erythroleukaemic cell line, also
identified the CCAAT box (-74/-70bp) as the primary cis-regulatory element involved
in ALDH1A1 transcription. However, in stark contrast to the its effect in T-cells,
HOX11 was shown to activate transcription in the HEL cell line, both from the empty
pGL3Basic luciferase reporter vector and from the ALDH1A1 promoter, in a manner
independent of the homeodomain DNA binding helix 3. HOX11 thus appears to be a
dichotomous regulator, capable of both transcriptional activation and repression
depending on the circumstances. The mechanisms underlying these two functions are
also appear to be distinct, with repression but not activation requiring the presence of
homeodomain helix 3.
ALDH1A1 encodes an enzyme involved in the irreversible conversion of retinaldehyde
to the biologically active metabolite, retinoic acid (RA) and appears to be
physiologically regulated by Hox11 in the developing spleen. Since RA is a potent
modulator of cellular differentiation, proliferation and apoptosis, the dysregulation of
RA synthesis is likely to have severe consequences for the cell and may constitute a
mechanism whereby overexpression of HOX11 predisposes T-cells to malignant transformation.
FHL1 also appears to have potential relevance to tumorigenesis, given
that it encodes protein isoforms with suspected roles in transcriptional regulation. As a
starting point to investigate a possible link between these HOX11 target genes and
leukaemogenesis, the effect of overexpressing ALDH1A1 and FHL1 on murine
haematopoiesis was assessed following reconstitution of lethally irradiated mice with
retrovirally-transduced primary murine bone marrow cells. The enforced expression of
ALDH1A1 in bone marrow was associated with a marked increase in myelopoiesis and a
decrease in B and T-lymphopoiesis. By contrast, overexpression of FHL1 was not
associated with perturbations in myelopoiesis or lymphopoiesis, although a slight
increase in erythropoiesis was observed in the bone marrow. While further work is
required to clarify the possible oncogenic roles of both of these HOX11 target genes,
these findings have served to identify ALDH1A1 in particular, as a gene which could
potentially be involved in HOX11-mediated tumorigenesis.
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The Effects of Aldehydehydrogenase1A1 on Immunoglobulin Production in MiceMayeku, Jukie K. 28 September 2010 (has links)
No description available.
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Role of Vitamin A Metabolism in Visceral ObesityYasmeen, Rumana 19 December 2012 (has links)
No description available.
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Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable TargetQuattrini, L., Sadiq, Maria, Petrarolo, G., Maitland, N.J., Frame, F.M., Pors, Klaus, La Motta, C. 10 December 2020 (has links)
Yes / Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.
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Towards the development of fluorescent probes targeting aldehyde dehydrogenase (ALDH) in cancer : expression and epigenetic modulation of ALDH1A1, ALDH2 and ALDH3A1 in selected in vitro modelsCosentino, Laura January 2012 (has links)
The cancer stem cell (CSC) concept is still very controversial; therefore identification and isolation of this specific population remain challenging. A variety of putative markers have been described and measurement of high aldehyde dehydrogenase (ALDH) activity has been defined as a characteristic of stem cells (SCs). In this study, a library of novel small molecules (1,4-disubstituted acetalanthraquinones, AAQs), containing an acetal group as protected aldehyde functionality, was designed with the aim of probing affinity for ALDH metabolism and demonstrating their potential as molecular fluorescent probes to identify CSCs. The AAQs were shown to be subjective to acidic hydrolysis using 2M HCl at 37ºC; however compounds containing secondary or tertiary amine functionalities in their sidechain were only partly hydrolysed at 70 ºC. Metabolism studies were conducted using cytosolic fractions from rat liver enriched in ALDHs, yeast ALDH and human recombinant ALDH1A1. Some evidence was demonstrated which linked ALDH metabolism with aldehyde functionalities of hydrolysed AAQs (HAAQs). The AAQs were shown to emit far-red fluorescence (600-750 nm). A close relationship between structure modifications and alteration of cellular localisation, with gained specificity for selected sub-cellular compartments were achieved when assessed in A549 and U-2 OS cell lines. Thermal DNA denaturation and chemosensitivity assays were used to obtain information about DNA binding properties and cytotoxicity of AAQs and HAAQ congeners. All compounds were shown to be weak-to-moderately binding to DNA, and symmetrical 1,4-disubstituted compounds were shown to be non-toxic (IC50 = 100 :M) with nonsymmetrical analogues generating IC50 values in the 1-100 :M range. No fundamental variation in the biological activity was observed when comparing AAQs with HAAQs in the A549 (+ALDH) and MCF7 (-ALDH) cell lines. A pilot investigation revealed that aberrant gene methylation was cell-type dependent for three ALDH isoforms (1A1, 2, 3A1). Decitabine treatment led to enhanced protein expression for ALDH1A1 (A549), ALDH2 (MCF7) and ALDH3A1 (A549). In contrast, the protein level was reduced for ALDH1A1 in HT29 cells after decitabine treatment. ALDH1A1, ALDH2 and ALDH3A1 were highly expressed in prostate cell lines, with expression linked to promoter methylation. In contrast, low levels of DNA methylation were found in primary prostate cancer cells and benign prostatic hyperplasia. Interestingly, ALDH1A1, considered a SC marker, was found to be expressed at low levels in CD133⁺/ α₂β₁ hi stem cell fraction and upregulated in CD133⁻/ α₂β₁ lo differentiated prostate cancer cells. In summary, the results in this thesis demonstrate the complexity and tumour type specificity of ALDH expression. This creates challenges for the development of selective probes for CSC isolation, such as the AAQs discussed in this thesis. Although inconclusive results were obtained in regard to AAQs and their potential in targeting ALDHs, selected AAQs were shown to reveal interesting biological features highlighting them as potential non-invasive cytometric probes for tracking molecular interactions in live cells.
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Towards the development of fluorescent probes targeting aldehyde dehydrogenase (ALDH) in cancer. Expression and epigenetic modulation of ALDH1A1, ALDH2 and ALDH3A1 in selected in vitro models.Cosentino, Laura January 2012 (has links)
The cancer stem cell (CSC) concept is still very controversial; therefore identification and isolation of this specific population remain challenging. A variety of putative markers have been described and measurement of high aldehyde dehydrogenase (ALDH) activity has been defined as a characteristic of stem cells (SCs). In this study, a library of novel small molecules (1,4-di-substituted acetalanthraquinones, AAQs), containing an acetal group as protected aldehyde functionality, was designed with the aim of probing affinity for ALDH metabolism and demonstrating their potential as molecular fluorescent probes to identify CSCs. The AAQs were shown to be subjective to acidic hydrolysis using 2M HCl at 37ºC; however compounds containing secondary or tertiary amine functionalities in their sidechain were only partly hydrolysed at 70 ºC. Metabolism studies were conducted using cytosolic fractions from rat liver enriched in ALDHs, yeast ALDH and human recombinant ALDH1A1. Some evidence was demonstrated which linked ALDH metabolism with aldehyde functionalities of hydrolysed AAQs (HAAQs). The AAQs were shown to emit far-red fluorescence (600-750 nm). A close relationship between structure modifications and alteration of cellular localisation, with gained specificity for selected sub-cellular compartments were achieved when assessed in A549 and U-2 OS cell lines. Thermal DNA denaturation and chemosensitivity assays were used to obtain information about DNA binding properties and cytotoxicity of AAQs and HAAQ congeners. All compounds were shown to be weak*to*moderately binding to DNA, and symmetrical 1,4-di-substituted compounds were shown to be non*toxic (IC50 = 100 :/! with non-symmetrical analogues generating IC50 values in the 1-100 :/ range. No fundamental variation in the biological activity was observed when comparing AAQs with HAAQs in the A549 (+ALDH) and MCF7 (-ALDH) cell lines. A pilot investigation revealed that aberrant gene methylation was cell-type dependent for three ALDH isoforms (1A1, 2, 3A1). Decitabine treatment led to enhanced protein expression for ALDH1A1 (A549), ALDH2 (MCF7) and ALDH3A1 (A549). In contrast, the protein level was reduced for ALDH1A1 in HT29 cells after decitabine treatment. ALDH1A1, ALDH2 and ALDH3A1 were highly expressed in prostate cell lines, with expression linked to promoter methylation. In contrast, low levels of DNA methylation were found in primary prostate cancer cells and benign prostatic hyperplasia. Interestingly, ALDH1A1, considered a SC marker, was found to be expressed at low levels in CD133+/ α2β1hi stem cell fraction and upregulated in CD133-= α2β1lo differentiated prostate cancer cells. In summary, the results in this thesis demonstrate the complexity and tumour type specificity of ALDH expression. This creates challenges for the development of selective probes for CSC isolation, such as the AAQs discussed in this thesis. Although inconclusive results were obtained in regard to AAQs and their potential in targeting ALDHs, selected AAQs were shown to reveal interesting biological features highlighting them as potential non-invasive cytometric probes for tracking molecular interactions in live cells. / EPSRC, Biostatus / The full text was made available at the end of the re-embargo period, 1st September 2017.
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Targeting Cancer Stem-LIike Cells in Human Esophageal Squamous Carcinoma Cell Lines by CurcuminAlmanaa, Taghreed N. 16 December 2013 (has links)
No description available.
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Bidirectional regulation of YAP and ALDH1A1Martien, Matthew F. 10 August 2015 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Breast cancer is the second leading cause of cancer death for women in the United States. Approximately, 1 in 5 women will recur with cancer within 10 years of completing treatment and recent publications have suggested that breast cancer stem cells confer resistance to therapy. These reports highlight aldehyde dehydrogenase 1A1 (ALDH1A1) and Yes-associated protein (YAP) as a biomarker and key mediator of the stem cell phenotype respectively. To further understand how YAP and ALDH1A1 facilitate chemoresistance, this study investigated how ALDH1A1 specific inhibition affected YAP activity and growth of basal-like breast cancer cells, which are enriched in cancer stem cells. Intriguingly, attenuation of growth by ALDH1A1 inhibition was observed when cells were plated on a reconstituted basement membrane. Further, the inhibition of cell growth correlated with cytosolic retention of YAP and a reduction in YAP signaling. In a complementary analysis, the overexpression of YAP correlated with an increased level of ALDH1A1 transcript. Results from this study indicate a novel mechanism by which basal-like breast cancer cells utilize YAP to maintain the stem cell phenotype and also suggest ALDH1A1 as a potential therapeutic target for breast cancer therapy.
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Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic DisordersDiSilvestro, David Joel January 2015 (has links)
No description available.
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