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Np63
and TAp63 Regulate Transcription of Genes with Distinct Biological Functions in Cancer and Development1
Departments of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196 [G. W., S. N., M. H., M. O., C-C. R. L., S. M. D., Z. G., N. B., Y. C., P. R., J. C., C. M., D. S., B. T.]; Laboratory of Population Genetics, National Cancer Institute, Rockville, Maryland [T. D., J. J.]; and Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196 [E. R.]
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ABSTRACT |
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Np63. Each type yields three isotypes (
, ß, 
) because of differential splicing of the p63 COOH terminus. The purpose of this study was to determine whether there is a functional link between the distinct p63 isotypes in their transcriptional regulation of downstream targets and their role in various cellular functions. TAp63 and Np63 adenovirus expression vectors were introduced into Saos2 cells for 4 and 24 h, and then gene profiling was performed using a DNA microarray chip analysis. Seventy-four genes (>2-fold change in expression) were identified that overlapped between two independent studies. Thirty-five genes were selected for direct expression testing of which 27 were confirmed by reverse transcription-PCR or Northern blot analysis. A survey of these genes shows that p63 can regulate a wide range of downstream gene targets with various cellular functions, including cell cycle control, stress, and signal transduction. Our study thus revealed p63 transcriptional regulation of many genes in cancer and development while often demonstrating opposing regulatory functions for TAp63 and Np63. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Np63 and Np73; Refs. 2
, 5
). In addition, both of these genes undergo alternative splicing at the COOH terminus, giving rise to three isotypes (, ß, ; Refs. 1
, 4
, 6
). The -isotypes of both p63 and p73 contain an extended COOH terminus with a conserved SAM domain implicated in protein-protein interactions (7)
. In general, the TAp63 (TAp73) isotypes might behave like p53 because they transactivate various p53 downstream targets, induce apoptosis, and mediate cell cycle control. However, the Np63 (Np73) isotypes have been shown to display opposing functions vis-à-vis the TAp63 (TAp73)-isotypes, including acting as oncoproteins (8, 9, 10, 11, 12)
.
To better understand both the targets of the p63 gene transcriptional regulation and the functional differences between the TA and the N isoforms, we undertook the task of looking for downstream targets of p63 using cDNA microarray technology. We found that p63 can regulate genes with diverse roles in cellular function and possesses opposing regulatory effects based on the expression of two main p63 isotypes.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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(p51B) and Np63 (CUSP) were each subcloned into the shuttle vector, pAdTrack-CMV. The resultant plasmids, pCMV-TAp63 or pCMV-Np63, were cotransformed into electrocompetent Escherichia coli (strain BJ5183) cells together with an adenoviral backbone plasmid, pAdEasy-1. Cells were selected for kanamycin resistance, and homologous recombination was confirmed by restriction digest analysis. The linearized plasmids were transfected into HEK-293 using Lipofectamine-2000 (Invitrogen). Final yields of Ad-TAp63 and Ad-Np63 were generally 1011–1012 plaque-forming units (11)
.
Cell Lines and RNA Preparation.
Human osteosarcoma cell line Saos2 (p53-null, no p63 expression) was obtained from American Tissue Culture Collection and grown at 37°C in humidified 5% CO2 in RPMI 1640 (Invitrogen) supplemented with 10% fetal bovine serum. Cells (107) were infected with an empty adenovirus Ad5, Ad-TAp63, or Ad-Np63 (each one with multiplicity of infection = 1). Total RNA was extracted with the Trizol reagent (Life Technologies, Inc.) after different time periods after adenovirus infection. Quality of RNA preparations was evaluated with a denaturing 2% agarose electrophoresis. To evaluate expression of p63 isotypes at 2, 4, 8, 12, 24, and 36 h of adenovirus infection, we tested p63 protein levels by Western blotting using 4A4 antibody (Santa Cruz Biotechnology).
Biotinylated RNA Probe Preparation and Hybridization.
Hu95A.V2 DNA chip arrays (Affymetrix) containing 12,500 human genes were used for gene expression profiling. Seven µg of total RNA were used for the preparation of double-stranded cDNA using a Superscript choice system and an oligo(dT)24-anchored T7 primer (Invitrogen). The cDNA was then used as a template to synthesize a biotinylated cRNA for 5 h at 37°C with aid of the BioArray High Yield RNA Transcript Labeling Kit (Enzo Diagnostics, Inc.). In vitro transcription products were purified using RNeasy spin columns (Qiagen). Biotinylated RNA was then treated for 35 min at 94°C in a buffer composed of 200 mM Tris-acetate (pH 8.1), 500 mM potassium acetate, and 150 mM magnesium acetate. Affymetrix HU95A-V2 array chips were hybridized with biotinylated cRNA (15 µg/chip) for 16 h at 45°C using the hybridization buffer and control provided by manufacturer (Affymetrix). GeneChip Fluidics station 400 (Affymetrix) was used for washing and staining the arrays. A three-step protocol was used to enhance the detection of the hybridized biotinylated cRNA. Firstly, an incubation with a streptavidin-phycoerythrin conjugate followed by labeling with an anti-streptavidin goat-biotinylated antibody (Vector Laboratories) and a final staining again with the streptavidin-phycoerythrin conjugate. The chips were then scanned using a specific scanner (Hewlett Packard). The excitation source was an argon ion laser, and a photomultiplier tube detected the emission through a 570-nm long pass filter. Digitized image data were processed using the GeneChip software (version 3.1) available from Affymetrix.
GeneChip Data Analysis.
Average difference values from each individual chip were scaled such that the average intensity of any given chip was 2500. We discarded genes that were scored absent in each sample according to the Affymetrix Array Suite software package. To identify specific genes misexpressed in samples infected with Ad-TAp63 or Ad-Np63 relative to control Ad5-infected samples, we generated a computer algorithm allowing us to select genes exhibiting 
2-fold expression change in all of our experimental samples relative to control (Ad5 only). We used three biological replicas for each of our samples and considered the genes for additional analysis, showing a common pattern of fold changes in each of the three individual experiments.
RT-PCR and Western Blotting.
RT-PCR analysis was carried out essentially as described previously (sequences of RT-PCR primers and PCR conditions will be provided on request; Ref. 13
). For immunoblotting, protein concentrations in all of the samples were equalized after measurement with the Bio-Rad protein assay kit. We used the following antibodies: a mouse monoclonal antibody against Hsp-70 (NeoMarkers); ß-actin (Sigma); c-fos; and a rabbit polyclonal antibody against FGFR2 (Santa Cruz Biotechnology). Horseradish peroxidase-conjugated secondary antibodies were sheep antimouse and donkey antirabbit immunoglobulins (Amersham-Pharmacia Biotech). Signals were detected with an enhanced chemiluminescence detection kit (Amersham-Pharmacia Biotech) according to the manufacturer’s protocol.
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Results and Discussion |
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Np63 or TAp63 cDNA under expression of the cytomegalovirus promoter. Because Saos2 cells are p53 null and do not express endogenous p63 (11)
, we anticipated that target genes expressed after such infection would be directly attributable to ectopic p63 expression. On the basis of expression studies of our adenovirus with other genes (data not shown), we also decided to test two time points: an early time point of 4 h and a late time point of 24 h after adenovirus infection. Of the various p63 isotypes available, we used TAp63, which is the longest isotype and Np63 without a TA domain, and also the most abundant p63 isotype expressed in tumor cells (Fig. 1A
; Refs. 11
, 14, 15, 16
). As a negative control, we used the same cells infected with an empty adenovirus vector. At different time points after infection, total protein lysates were analyzed for p63 protein levels by denaturing protein gel electrophoresis followed by Western blotting to confirm expression of each p63 isotype used in this study (Fig. 1B)
. As a control for viability of cells after adenovirus infection, we tested and normalized to ß-actin protein levels (Fig. 1B)
. Moreover, each time point was tested twice, and each experiment was repeated from infection to cDNA microarray analysis under the same conditions. Only those genes that were identified independently in both experiments are listed in Table 1
. To additionally confirm these results, we performed Northern blot hybridization analysis or semiquantitative PCR and/or Western blotting on 35 candidate genes and confirmed >2-fold change in 27 genes. Twenty-two (either cancer or development related) of these 27 genes are shown in Table 2, A and B
. In addition, we tested 10 other potential targets (by RT-PCR) identified on individual microarray results that did not meet all of the above criteria, 6 of which were positive by RT-PCR and also listed in Table 2
.
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consists of 74 genes transcriptionally regulated by p63 and divided into various groups for convenience based on gene function. These groups include cell cycle control, DNA repair, signal transduction, oncogenes and/or tumor suppressor genes, transcription factors, receptors, growth factors or growth inhibitors, stress, development/metabolism, and structural proteins. Ordinary positive numbers represent genes that were up-regulated after p63 infection and minus signs represent down-regulation by a p63 isotype at that particular time point. Approximately 60% of the genes were up-regulated and 40% down-regulated by either Np63 or TAp63. From Table 1
it can be seen that the expression levels of 53 genes were altered by Np63 compared with 23 genes by TAp63. The most prominent genes up-regulated by Np63 were various members of the Hsp-70 family (
15–28 fold; Ref. 17
), and ketohexokinase (-52 fold; Ref. 18
). The most prominent genes down-regulated by Np63 were the oncogene c-fos (4.6 fold), type VI collagen -3 (5.8 fold; Ref. 19
), and an adipogenesis inhibitory factor (IL-11 homologue (5.2 fold; Ref. 20
).
Of the genes up-regulated by TAp63 the most prominent were the oncogenes, muscle aponeurotic fibrosarcoma oncogene homolog F (5.9 fold; Ref. 21
), and acute myelogenous leukemia (5.2 fold; Ref. 22
). TAp63 down-regulated IL-8 (58-fold; Ref. 23
), ß-thromboglobulin (50-fold; Ref. 24
), and LNK (7.9 fold), an adaptor protein that can inhibit T-cell activation (25)
. There was little overlap between the genes differentially expressed by both p63 isotypes (Table 1)
. In fact, of the genes confirmed by either RT-PCR or Northern blot hybridization, no direct correlation between these two p63 isotypes was seen, consistent with the idea that the TAp63 and Np63 isotypes have different functional roles in the cell. In addition, 12 genes showed an inverse correlation between the two isoforms, suggesting that these isoforms can also have opposing functions (Table 2)
.
This list may be considered as a partial profile of genes, which are either directly or indirectly regulated by p63. We listed expression profiles of two of six different p63 isotypes in one cell line. A more comprehensive list would also include downstream targets of all of the isoforms of p63 in a variety of cell types. However, this list remains impressive as many key genes from several different functional categories are clearly candidates for transcriptional regulation by p63.
p63 Plays a Role in Cell Cycle Control.
PCTAIRE 2 and PCTAIRE3, two downstream targets of p63, are cell cycle control-related genes and both of them were strongly (>3-fold) up-regulated by Np63 and down-regulated by TAp63 (Fig. 1C)
. The PCTAIRE protein kinases are an extended gene family encoding many different cdc2-related serine/threonine-specific protein kinases and are so named for the presence of a cysteine-for-serine substitution in the conserved PSTAIRE amino acid motif found in prototypic cdc2 kinases. Three members of this kinase subfamily, PCTAIRE 1–3, were identified in humans, whereas only two members were identified in mice, PCTAIRE1 and PCTAIRE3 (26
, 27) . TAp63 and Np63 show opposite effects on these two cell cycle genes. Activation of the cyclin-dependent kinase 2 gene family leads to cell proliferation, and therefore, it is not surprising that Np63 as a potential oncogene would up-regulate, whereas TAp63 would down-regulate this function. The expression pattern of other cell cycle-related genes including cyclin G1, cyclin G2, cyclin T1, and cyclin T2ß were also checked by RT-PCR, but no significant changes were confirmed, although the microarray data showed at least a 2-fold change. This can be explained by the limited sensitivity of the RT-PCR in detecting minor changes at the RNA level. It is also possible that p63 is predominantly involved in cell cycle control through regulation of PCTAIRE members.
p63 Regulates Multiple Signaling Pathways.
Two notch ligands, JAG1 and JAG2, were identified by the cDNA microarray as up-regulated in TAp63 infected cells. This result was confirmed by RT-PCR, which in addition, showed that Np63 down-regulates JAG2 but not JAG1 (Fig. 1C)
. Our results confirm previous studies that JAG1 and JAG2 genes are up-regulated by p63 and p73 (28)
. Furthermore, investigators identified a p63-binding site in the second intron of the JAG1 gene, which can directly interact with the p63 protein in vivo, as assessed by a chromatin immunoprecipitation assay. JAG1 and JAG2 were also up-regulated by TAp63, suggesting that TAp63 may have much stronger transcriptional activity than TAp63 (28)
. Taken together with our data, these studies highlight a potential role of p63 in the Notch pathway.
We also observed a role for p63 in the Wnt pathway. Both DNA chip microarray analysis and RT-PCR demonstrated that Np63 up-regulates hDKK expression at the RNA level (Tables 1
and 2
, Fig. 1C
). However, TAp63 had no effect on the hDKK1 transcription (Tables 1
and 2)
. The hDKK gene encodes a secreted glycoprotein that binds to the extracellular domain of LRP5/6 and, in turn, prevents the formation of the active Wnt-Frizzled-LRP5/6 receptor complexes (29)
. Recently, p53 was reported to transcriptionally activate the hDKK gene (30)
. Although p53 and Np63 often demonstrate opposing functions, in this case, they appear to up-regulate the same target. By additional RT-PCR analysis, we failed to find any significant changes in the RNA levels of other genes associated with the Wnt pathway, including Frizzled, Dishevelled, glycogen synthase kinase-3ß, and ß-catenin.
Effects of P63 on Proliferation, Apoptosis, Stress, and Angiogenesis Factors.
The c-fos proto-oncogene is a member of multigene family encoding a transcriptional factor, which dimerizes with the Jun family proteins c-Jun, JunB, and JunD to form the transcription factor complex activator protein 1 (31
, 32)
. The c-fos protein has been implicated as a key molecule in cell differentiation, proliferation, and transformation. In addition, the c-fos protein has been associated with apoptosis. Moreover, the c-fos gene has been shown to be a target for TA by p53. In mice, this TA of c-fos by p53 is not through the 5' basic promoter but through the p53-responsive element located in its first intron (32)
. Our study showed that TAp63 up-regulates the c-fos gene (as early as 4 h), whereas both Np63 and p40 (the smallest Np63 isotype) down-regulate this gene at the RNA and protein levels (Fig. 2, A and B)
. We failed to find any cis-elements in either the 5' basic promoter or in the first intron of c-fos using a luciferase reporter assay (data not shown). This may reflect a difference between human and mouse c-fos regulation by p53 and p63.
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up-regulated the PIG3 gene 3-fold (Table 2
and Fig. 1C
), suggesting that TAp63 and p53 may be involved in the same apoptotic pathway through their interaction with the PIG3 gene.
One of the most consistent and strongly up-regulated genes exclusively mediated by Np63 is the Hsp-70 (17)
. In general, Hsp’s function is to protect cells from adverse stresses, be it environmental, chemical, or physical. Hsps prevent protein aggregation and promote the refolding of denatured proteins. It is now thought that several members of this family, including Hsp-70, can and do play an antiapoptotic role and thereby protect cells from death after DNA damage or stress (17)
. In normal cells, sublethal damage may activate the antiapoptotic function of Hsp-70 and maintain cell survival (in a nondividing state) until the damage has been repaired and the cell can then resume its normal function. However, an increase in Hsp-70 expression in tumor cells might maintain inappropriate cell survival, promoting damage retention and tumorigenesis. Because Np63 but not TAp63 up-regulates Hsp-70, this observation additionally supports an oncogenic role for Np63.
The induction of new blood vessels or angiogenesis plays a major role in tumor formation and metastasis. RT-PCR results suggest that both p63 isotypes used in these studies influence two genes known to play a role in angiogenesis, namely, VEGF (34)
and IL-8 (23)
. VEGF binds specific receptors on vascular endothelial cells and thereby promotes both proliferation and neovascularization. Interestingly, TAp63 led to down-regulation of this gene, whereas Np63 had no effect.
However, although others have supported repression of VEGF by TAp63, they also reported up-regulation by Np63 (35)
. IL-8’s role in cancer is through its mitogenic and angiogenic activities (23
, 34
, 36)
. By RT-PCR, we show that Np63 up-regulates IL-8 (Fig. 1C)
. However, we could not confirm the down-regulation of IL-8 by TAp63 as seen in the microarray results (Table 1)
. These results suggest a possible connection between p63 and angiogenesis and need to be additionally investigated.
The Involvement of p63 in Skin Differentiation and Morphogenesis.
Seminal studies, based on generation of p63-knockout mice, clearly established a critical role of p63 gene in differentiation of stratified squamous epithelia leading to severe defects in skin development, skin renewal, and hair follicle morphogenesis (37
, 38) . For this reason, it is noteworthy that hair keratin acidic3–11 (type I keratin) and keratin-6e are regulated by TAp63, as shown by cDNA microarray studies and RT-PCR (Table 2
and Fig. 1C
). Hair keratin acidic3–11 is abundantly expressed in the hair follicle and constitutes the elemental keratin profile of cortex cells (39)
. In addition, the type II keratin 6 is constitutively expressed in distinct types of epithelia, including the outer root sheath of hair follicles (40)
. Therefore, our data implicates p63 in the development of the hair follicle.
BPAG1 is a glycoprotein that is one of the components of the basement membrane zone of skin. BPAG1 is made by stratified squamous epithelia, where it localizes to the inner surface of specialized integrin-mediated adherens junctions (hemidesmosomes). In BPAG1-knockout mice hemidesmosomes were found to be normal, but they lacked the inner plate and had no cytoskeleton attached (41)
. This change compromised the mechanical integrity of epithelia and influenced cell migration without affecting cell growth or adhesion to substrate. Our study indicates that TAp63 up-regulates the BPAG1 gene expression (Table 2
and Fig. 1C
), additionally supporting the importance of p63 in normal skin development and function.
In addition, FGFR2 was up-regulated by TAp63 and down-regulated by Np63 (Table 2)
with verification by RT-PCR and Western blotting (Fig. 2, C and D)
. We also tested FGFR1 and FGFR3 expression by independent RT-PCR analysis, but no significant changes were detected (data not shown). Interestingly, the expression level of several other players of FGF signaling (FGF1, FGF9, FGF18, FGFR1, and FGFR4) were also seen to change, albeit much less (1.2–1.9 fold) in response to p63 overexpression in one or both of our two independent microarray studies. As shown earlier, the p63 gene is essential for limb, craniofacial, and epithelial development (37
, 38)
. FGFRs have been reported to function in cranial suture morphogenesis, calvarial bone development, eyelid, and skin formation (42
, 43)
. Previous studies have shown that FGFR2 is less likely to act upstream of the p63 gene, and therefore, it was suggested that p63 and FGFR2 might control two parallel pathways in skin initiation and development (42)
. However, our study clearly shows that FGFR2 functions as a downstream target of p63, suggesting that the latter might be involved in limb development and/or skin formation through regulation of the FGF-signaling pathway.
Aldehyde dehydrogenase 6 gene is up-regulated by TAp63 and down-regulated by Np63 (Fig. 1C)
. This gene has also been shown to be important in development (44)
. It controls one of the steps involved in the generation of retinol (vitamin A) to RA. A defect in RA synthesis might be involved in the transformation process, and RA has been used to reverse such changes (45)
. TAp63 up-regulates this gene, whereas Np63 leads to its down-regulation. Moreover, p53 was shown to activate this gene (46)
, supporting the notion of overlap between p53 and TAp63 function.
Similarities and Differences between p53 and p63 Isotypes.
As expected, some p53-responsive genes were also identified here as targets of p63. These genes include PIG3, p21, JAG1, JAG2, c-fos, ephrin A4, IGBP3, and ERCC5 (Tables 1
and 2)
. The existence of common targets for both p53 and p63 indicates that p53 and p63 are not only structurally similar but are also involved in common cell signaling pathways. However, p63 failed to activate most known p53 targets identified by various approaches (Table 2
; Refs. 47
, 48
). This may reflect functional differences between p53 and p63 but also may be caused by the variable conditions used in the different analyses.
In contrast to TAp63 isotypes, Np63 isotypes lack a TA domain, which led to the notion that Np63 proteins do not possess TA properties (4)
. However, Np63 isotypes were shown to directly activate specific gene targets (48)
and, together with our results, support the idea that Np63 may possess direct or indirect transcriptional activity on specific genes in certain cell types. To verify this hypothesis, we tested the ability of TAp63 or Np63 to affect the Hsp-70 gene promoter activity using a luciferase reporter assay in Saos2 cells. The results show that Np63 has much stronger transcriptional activity (10 fold) than TAp63 on the Hsp-70 promoter (data not shown). This result confirmed our microarray data, RT-PCR analysis, and Western blotting, which showed that the Hsp-70 and Hsp-70B genes were up-regulated by Np63 but not by TAp63 (Fig. 2, C and D)
. We have previously demonstrated critical protein-protein interactions between Np63 and p53 (10)
. Because Saos2 cells lack p53, the p63 activity shown here was not attributable to abrogation of p53 transcriptional activity. We have not shown that this is a result of direct Np63 binding to the promoter nor excluded protein-protein interactions. Regardless, Np63 expression clearly leads to activation of specific downstream targets.
TAp63 and Np63 seem on the whole to influence a different plethora of genes (Table 2
and Fig. 1C
) and, consequently, may have opposite or different roles to play in the cell. This is in agreement with the idea that the TAp63 isotypes play a more p53-like role, whereas the Np63 isotypes have a more opposing effect or even an inherent oncogenic role in cancer progression (4
, 10
, 11
, 49)
. Our data suggests that these opposing effects are likely to be involved in many different cellular processes, including cell cycle control, apoptosis, proliferation, and cell migration, and each of these functions deserves additional detailed study in normal development and cancer formation.
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ACKNOWLEDGMENTS |
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Np63) cDNA, and Shuntaro Ikawa (Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan) for TAp63 (p51b). |
FOOTNOTES |
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1 This work was supported, in part, by these grants: National Cancer Institute-Lung Cancer SPORE Grant CA-58184-01 (to D. S., B. T.), National Institute of Dental and Craniofacial Research Grant R01-DE 012588-0 (to D. S., E. R., B. T.), National Institute of Allergy and Infectious Diseases Grant R01-AI47224-01 (to E. R.), American Cancer Society Grant RPG-TBE-98317 (to E. R.), Traylor Research Fund and the Lilly Clinical Investigator Award of the Damon Runyon Foundation (to J. C.), and the Clinical Innovator Award from the Flight Attendant Medical Research Institute (to J. C.). 
2 These authors contributed equally to this manuscript.
3 To whom requests for reprints should be addressed, at Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, 818 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. Phone: (410) 502-5153; Fax: (410) 614-1411; E-mail: dsidrans@jhmi.edu or btrink{at}jhmi.edu
4 The abbreviations used are: TA, transactivation; RT-PCR, reverse transcription-PCR; Hsp, heat shock protein; IL, interleukin; JAG1, Jagged 1; JAG2, Jagged 2; VEGF, vascular endothelial growth factor; BPAG1, bullous pemphigoid antigen 1; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; RA, retinoic acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SAM, sterile alpha motif.
Received 11/12/02. Accepted 3/28/03.
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 T. M. Caserta, R. Kommagani, Z. Yuan, D. J. Robbins, C. A. Mercer, and M. P. Kadakia p63 Overexpression Induces the Expression of Sonic Hedgehog Mol. Cancer Res., October 1, 2006; 4(10): 759 - 768. [Abstract] [Full Text] [PDF]
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B.-C. Nguyen, K. Lefort, A. Mandinova, D. Antonini, V. Devgan, G. Della Gatta, M. I. Koster, Z. Zhang, J. Wang, A. T. di Vignano, et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation Genes & Dev., April 15, 2006; 20(8): 1028 - 1042. [Abstract] [Full Text] [PDF]
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 J. Laurikkala, M. L. Mikkola, M. James, M. Tummers, A. A. Mills, and I. Thesleff p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation Development, April 15, 2006; 133(8): 1553 - 1563. [Abstract] [Full Text] [PDF]
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 B. Testoni and R. Mantovani Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63 Nucleic Acids Res., February 9, 2006; 34(3): 928 - 938. [Abstract] [Full Text] [PDF]
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 K.E. King, R.M. Ponnamperuma, M.J. Gerdes, T. Tokino, T. Yamashita, C.C. Baker, and W.C. Weinberg Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis Carcinogenesis, January 1, 2006; 27(1): 53 - 63. [Abstract] [Full Text] [PDF]
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J.-C. Bourdon, K. Fernandes, F. Murray-Zmijewski, G. Liu, A. Diot, D. P. Xirodimas, M. K. Saville, and D. P. Lane p53 isoforms can regulate p53 transcriptional activity Genes & Dev., September 15, 2005; 19(18): 2122 - 2137. [Abstract] [Full Text] [PDF]
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W. M. Keyes, Y. Wu, H. Vogel, X. Guo, S. W. Lowe, and A. A. Mills p63 deficiency activates a program of cellular senescence and leads to accelerated aging Genes & Dev., September 1, 2005; 19(17): 1986 - 1999. [Abstract] [Full Text] [PDF]
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 M. MacPartlin, S. Zeng, H. Lee, D. Stauffer, Y. Jin, M. Thayer, and H. Lu p300 Regulates p63 Transcriptional Activity J. Biol. Chem., August 26, 2005; 280(34): 30604 - 30610. [Abstract] [Full Text] [PDF]
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R. A. Johnson, E. M. Shepard, and K. W. Scotto Differential Regulation of MDR1 Transcription by the p53 Family Members: ROLE OF THE DNA BINDING DOMAIN J. Biol. Chem., April 8, 2005; 280(14): 13213 - 13219. [Abstract] [Full Text] [PDF]
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 J. M. A. Moreira, G. Ohlsson, F. E. Rank, and J. E. Celis Down-regulation of the Tumor Suppressor Protein 14-3-3{sigma} Is a Sporadic Event in Cancer of the Breast Mol. Cell. Proteomics, April 1, 2005; 4(4): 555 - 569. [Abstract] [Full Text] [PDF]
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C. E. Barbieri, C. A. Perez, K. N. Johnson, K. A. Ely, D. Billheimer, and J. A. Pietenpol IGFBP-3 Is a Direct Target of Transcriptional Regulation by {Delta}Np63{alpha} in Squamous Epithelium Cancer Res., March 15, 2005; 65(6): 2314 - 2320. [Abstract] [Full Text] [PDF]
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G. Wu, M. Osada, Z. Guo, A. Fomenkov, S. Begum, M. Zhao, S. Upadhyay, M. Xing, F. Wu, C. Moon, et al. {Delta}Np63{alpha} Up-Regulates the Hsp70 Gene in Human Cancer Cancer Res., February 1, 2005; 65(3): 758 - 766. [Abstract] [Full Text] [PDF]
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J. Teuliere, M. M. Faraldo, M.-A. Deugnier, M. Shtutman, A. Ben-Ze'ev, J. P. Thiery, and M. A. Glukhova Targeted activation of {beta}-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia Development, January 15, 2005; 132(2): 267 - 277. [Abstract] [Full Text] [PDF]
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J. M. A. Moreira, P. Gromov, and J. E. Celis Expression of the Tumor Suppressor Protein 14-3-3{sigma} Is Down-regulated in Invasive Transitional Cell Carcinomas of the Urinary Bladder Undergoing Epithelial-to-Mesenchymal Transition Mol. Cell. Proteomics, April 1, 2004; 3(4): 410 - 419. [Abstract] [Full Text] [PDF]
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M. I. Koster, S. Kim, A. A. Mills, F. J. DeMayo, and D. R. Roop p63 is the molecular switch for initiation of an epithelial stratification program Genes & Dev., January 15, 2004; 18(2): 126 - 131. [Abstract] [Full Text] [PDF]
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 U. M. Moll The Role of p63 and p73 in Tumor Formation and Progression: Coming of Age Toward Clinical Usefulness: Commentary re: F. Koga et al., Impaired p63 Expression Associates with Poor Prognosis and Uroplakin III Expression in Invasive Urothelial Carcinoma of the Bladder. Clin. Cancer Res., 9: 5501-5507, 2003, and P. Puig et al., p73 Expression in Human Normal and Tumor Tissues: Loss of p73{alpha} Expression Is Associated with Tumor Progression in Bladder Cancer. Clin. Cancer Res., 9: 5642-5651, 2003. Clin. Cancer Res., November 15, 2003; 9(15): 5437 - 5441. [Full Text] [PDF]
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