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p63 and epithelial homeostasis: studies of p63 under normal, hyper-proliferative and malignant conditions
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: The p63 gene is a member of the p53 transcription factor family and can produce six different proteins using two promoters and differential splicing. Expression of p63 is required for proper formation of epithelial tissues. Studies on the transcriptional control of specific genes involved in cell survival, proliferation, differentiation and adhesion have revealed the contributions of p63 to the continuously renewing stratified epithelium. In this thesis, the aim was to improve our understanding of the roles of p63 in epithelial homeostasis by investigating expression of p63 in normal and benign hyper-proliferative epithelia and exploring the influence of p63 deregulation on cancer progression.

Materials and methods: Using quantitative real time RT-PCR and immunohistochemistry, we first examined the expression of different p63 isoforms in patients diagnosed with psoriasis - a benign hyper-proliferative and inflammatory skin disease. Afterwards, we investigated responses of p63 in psoriatic epidermis upon Narrowband-UVB (NB-UVB) phototherapy. At the same time, we studied the potential impact of p63 in carcinogenesis by searching for p63 transcriptional targets in a cell line derived from squamous cell carcinoma of the head and neck (SCCHN) - the sixth most common cancer worldwide with over-expression of the ∆Np63α protein as a common feature. p63 gene silencing and microarray were used to identify p63 regulated genes. Real time RT-PCR, western blot, immunohistochemistry, chromatin immunoprecipitation, transient transfection and reporter assays were performed to confirm specific genes as direct p63 targets.

Results: Significant down-regulation of p63 mRNA levels was found in psoriatic lesions compared to patients’ own clinically normal skin. Moreover, a trend of decreased TAp63 mRNA levels was seen in patients’ normal skin compared to age- and sex-matched healthy controls. Following NB-UVB phototherapy, an effective first line therapy for psoriasis, expression of p63 was not significantly affected. However, significant changes in p53, FABP5, miR-21 and miR-125b were found. Surprisingly, location and expression levels of p63 proteins detected by immunohistochemistry were similar under all skin conditions. A direct transcriptional regulation of TRAF4 by p63 was seen in the SCCHN cell line and we further found that the localization of the TRAF4 protein was associated with histological differentiation of SCCHN cells. However, unlike its over-expression in SCCHN, similar TRAF4 mRNA expression levels were seen in psoriatic lesions as compared to healthy controls. Besides TRAF4, a total of 127 genes were identified as potentially p63 regulated in the SCCHN cell line and strikingly, about 20% of these genes are involved in cell adhesion or migration.

Conclusions: Dysregulation of p63 isoforms in psoriatic epidermis, especially decreased TAp63 expression, and their resistance to NB-UVB phototherapy implicated a contribution of p63 to the psoriasis phenotype. Transcriptional regulation of genes involved in multiple biological pathways indicated that over-expression of p63 in SCCHN might account for altered cell differentiation, adhesion and migration, thus contributing to SCCHN. In conclusion, our studies have found additional mechanisms through which p63 guarded homeostasis of the established epithelium. Deregulation of p63 might play a role in distinct pathological conditions by participating in diverse cellular pathways under different microenvironments.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2010. , 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1353
Keyword [en]
p63, psoriasis, SCCHN, epithelium, homeostasis
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-33894ISBN: 978-91-7459-015-9 (print)OAI: oai:DiVA.org:umu-33894DiVA: diva2:318598
Public defence
2010-06-01, föreläsningssal E04, Building 6E, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2010-05-15 Created: 2010-05-09 Last updated: 2010-05-15Bibliographically approved
List of papers
1. Dysregulation of TAp63 mRNA and protein levels in psoriasis
Open this publication in new window or tab >>Dysregulation of TAp63 mRNA and protein levels in psoriasis
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2006 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 126, no 1, 137-141 p.Article in journal (Refereed) Published
Keyword
Adult, Aged, DNA-Binding Proteins, Down-Regulation, Epidermis/chemistry/metabolism, Female, Genes; Tumor Suppressor, Humans, Male, Middle Aged, Phosphoproteins/analysis/genetics/*metabolism, Protein Isoforms/metabolism, Psoriasis/genetics/*metabolism, RNA; Messenger/analysis/metabolism, STAT3 Transcription Factor/metabolism, Trans-Activators/analysis/genetics/*metabolism, Tumor Suppressor Protein p53/genetics/metabolism, Tumor Suppressor Proteins
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-6734 (URN)10.1038/sj.jid.5700010 (DOI)16417229 (PubMedID)
Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2017-12-14Bibliographically approved
2. Little effect on p63 but significant effect on miR-21 and miR-125b by NB-UVB phototherapy on psoriatic lesions
Open this publication in new window or tab >>Little effect on p63 but significant effect on miR-21 and miR-125b by NB-UVB phototherapy on psoriatic lesions
2010 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Psoriasis is an inflammatory skin disease in which dysregulation of p63, a member of the p53 family and crucial for skin development and maintenance, has been shown. Though currently incurable, many therapies are available including narrowband ultraviolet B (NB-UVB) phototherapy. To further elucidate the role of p63 in psoriasis and increase our understanding of the mechanisms of phototherapy, we studied the effects of NB-UVB treatment on p63 expression. Expression of p53 was also studied due to its functional role in the response of skin to UV. In addition, we investigated expression of miR-203, miR-125b and miR-21, as these microRNAs are p63 and/or p53 regulators and their involvement in psoriasis pathogenesis has previously been suggested. Skin biopsies from 12 psoriasis patients were collected before, during and at the final session of phototherapy. Real time RT-PCR and immunohistochemistry showed that epidermal p63 mRNA and protein levels were not significantly affected following phototherapy, whereas a significant increase in p53 mRNA expression and protein accumulation was found. NB-UVB treatment also significantly affected expression of miR-21 and miR-125b, whereas individual clinical improvement seemed related to p53 status only. Our results indicate that even though NB-UVB phototherapy causes diverse molecular changes, induction of p53 is pivotal for successful treatment of psoriasis, and unresolved p63 abnormality in the treated epidermis of psoriasis patients further indicate a role for p63 in psoriasis.

Publisher
49 p.
Keyword
psoriasis, epidermis, NB-UVB phototherapy, p63, p53, microRNA
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-33737 (URN)978-91-7459-015-9 (ISBN)
Available from: 2010-05-06 Created: 2010-05-04 Last updated: 2013-06-12Bibliographically approved
3. TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN
Open this publication in new window or tab >>TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN
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2007 (English)In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 6, no 12, 1979-1983 p.Article in journal (Refereed) Published
Abstract [en]

p63, a member of the p53 family, is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and some other tumors of epithelial origin. As a transcription factor, p63 can bind to p53-type response elements and there is some overlap between p53 family transcriptional targets. Tumor necrosis factor receptor associated factor 4 (TRAF4) is a p53 regulated gene which is overexpressed in many human carcinomas. We investigated the involvement of p63 in regulation of TRAF4 and the expression of the TRAF4 protein in SCCHN. Disrupting endogenous p63 expression resulted in downregulation of TRAF4 mRNA and protein in an SCCHN cell line. Endogenous p63 bound to the TRAF4 promoter in vivo and reporter assays showed that p63, p73 and p53 can all transactivate TRAF4, with TAp63 isoforms being the most potent activators. The level of TRAF4 activation by TAp63 was two-fold higher than by p53, and TRAF4 was ten-fold more responsive to TAp63 than another p63-target, IGFBP3. Nuclear expression of TRAF4 was seen in normal oral epithelium and highly/moderately differentiated SCCHN, whereas cytoplasmic expression of TRAF4 was seen in poorly differentiated SCCHN. These results indicate that TRAF4 is a common target of p53 family members and that localization of TRAF4 is associated with differentiation of SCCHN cells.

Keyword
Adult, Aged, Aged; 80 and over, Blotting; Western, Carcinoma; Squamous Cell/genetics/metabolism/*pathology, Cyclooxygenase 2/genetics/metabolism, DNA-Binding Proteins, Female, Genes; Tumor Suppressor, Head and Neck Neoplasms/genetics/metabolism/*pathology, Humans, Male, Membrane Proteins/genetics/metabolism, Middle Aged, Mouth Mucosa/*metabolism, Phosphoprotein Phosphatase, Phosphoproteins/metabolism, RNA; Messenger/genetics/metabolism, Receptor; Epidermal Growth Factor/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Smoking, Trans-Activators/metabolism, Tumor Markers; Biological/genetics/*metabolism, Tumor Suppressor Proteins, beta Catenin/metabolism
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-7337 (URN)18087216 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
4. p63 contributes to cell invasion and migration in squamous cell carcinoma of the head and neck
Open this publication in new window or tab >>p63 contributes to cell invasion and migration in squamous cell carcinoma of the head and neck
2008 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 263, no 1, 26-34 p.Article in journal (Refereed) Published
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-8316 (URN)10.1016/j.canlet.2007.12.011 (DOI)18194839 (PubMedID)
Available from: 2008-01-17 Created: 2008-01-17 Last updated: 2017-12-14Bibliographically approved

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