DOCSLIB.ORG

Tumor Protein P63 Is a Key Regulator of Skin Functions in Ectodermal Dysplasia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tumor Protein P63 Is a Key Regulator of Skin Functions in Ectodermal Dysplasia Central Journal of Dermatology and Clinical Research Review Article *Corresponding author Edward A Ratovitski, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Tumor Protein P63 is a Key Cancer Research Building-II, Room 5M05, 1550 Orleans Street, Baltimore, MD 21231, USA. Tel: 410-491-9802; Fax: 410-614-1411; E-mail: [email protected] Regulator of Skin Functions in Submitted: 29 October 2013 Accepted: 31 October 2013 Ectodermal Dysplasia Published: 04 November 2013 Copyright Edward A Ratovitski* © 2013 Ratovitski Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, USA OPEN ACCESS Abstract Keywords Tumor protein (TP)-p63 has been discovered as TP53 homolog more than fifteen • p63 years ago and has become a master regulator of skin development, proliferation and stem • MicroRNA cell maintenance. While TP53 is known to be the most mutated gene in human cancer, TP63 • Apoptosis mutations are mostly associated with the various types of ectodermal dysplasia. All TP53 • Cell cycle arrest family members, TP53, TP63 and TP73, function as transcription factors that regulate the cell • Autophagy cycle arrest, apoptosis, autophagy or metabolism through activation/repression of downstream • Epigenetics target genes or protein-protein interactions with other protein regulators of transcription and • Keratinocytes splicing. Several downstream target genes or protein interactors of TP63 are involved in the • Ectodermal dysplasia molecular mechanisms underlying the ectodermal dysplasia phenotypes. This mini-review underlines a few venues of investigations about the key role for TP63 in skin biology and pathology. INTRODUCTION TP63 proteins exert their functions through the transcriptional regulation (activation of repression) by binding Multiple molecular mechanisms are underlying the skin cell proliferation and differentiation, while the master gene in the direct control of the skin epithelial sheet architecture, stem cellto the renewal, specific cell downstream cycle arrest, gene apoptosis, targets, senescence,many of them autophagy, involved genes, tumor protein (TP)-p63 is being investigated for the last skin aging, cellular response to ultraviolet (UV)- irradiation, decadeinvolved [1-4]. in genetic TP63 andgene epigeneticencoding regulationtranscription of factorsskin-specific with thereby contributing to the molecular pathogenesis of several mutated in cancer, however is often mutated in heritable skin geneticand epigenetic diseases controls of skin of and thereof epithelial via enzymes tissues and[15-26]. microRNAs, Among disorders,the transactivation such as ectodermaldomain (TA-) dysplasia and without [3,4]. it TP63 (ΔN-), mutations is rarely TP63 responsive gene targets are the following genes implicated can cause several different disorders: ectrodactyly, ectodermal in skin development and functions: ALOX12B, AQP3, BPAG1, dysplasia and cleft lip/palate syndrome (EEC), ankyloblepharon- CASP14, CDH1, CLDN1, DLX3, 5 and 6, DSG, DSP, EVL, HBP1, IKK, ectodermal defects-cleft lip/palate syndrome (AEC), limb IVL, IRF6, KRT5, and 14, LSH, PPL, PERP, SATB1, TPRG1, and mammary syndrome (LMS), Acro-Dermato-Ungual-Lacrimal- ZNF750 [17,20,21,27-37]. Tooth syndrome (ADULT), Rapp- Hodgkin syndrome (RHS), and split hand/foot malformation (SHFM4) [1,3,4]. Each group TP63 also engages in numerous protein-protein interactions ability to bind TP63 responsive elements in gene promoters splicing, protein degradation, and signaling [6-8,10,38-40]. TP63 of mutations affects specific functions of TP63 protein, such its that contribute to chromatin remodeling, RNA transcription, RNA and to form protein/protein complexes with other regulatory of gene expression. For example, the AEC-derived TP63 components(DNA-binding (SAM domain), domain), to be as properly reviewed ubiquitinated in [5-10]. (TI-domain), mutationsassociates withaltered many the proteins ability involvedfor TP63 in to a fine-tunedphysically regulation associate The key studies show that tp63 null mice display single- leading to a deregulated splicing of FGFR2 receptor responsible forwith epithelial/mesenchymal mRNA processing/splicing transition proteins (EMT) (e.g. [6,8]. ABBP1, AEC-derived SRA4) leading to a breakage of the epidermal barrier formation that layered and translucent skin, with an altered stratified epithelia mutations in TP63 were also found to alter the TP63 binding to protects against dehydration [11,12]. Homozygous ΔNp63 null palate, and down regulation of PERP [38,39]. disorganized epithelial cells exhibiting a premature expression SATB2, which has been implicated in the development of cleft mice show under-developed stratified epidermis with clusters of TP63 is over expressed in multiple human epithelial cancers, expressing transgenic mice show an abnormal hair follicle including head and neck, esophagus and lung cancers, cervix and developmentof terminal differentiationand altered cell markersfate of follicular [13]. However,keratinocytes ΔNp63α [14]. breast tumors [40]. Accumulating evidence shows that TP63 Cite this article: Ratovitski EA (2013) Tumor Protein P63 is a Key Regulator of Skin Functions in Ectodermal Dysplasia. J Dermatolog Clin Res 1(1): 1006. Ratovitski (2013) Email: [email protected] Central and especially its ∆ ∆ N isoforms play a critical role in head and remodeling complexes, noncoding microRNAs implicated in neck squamous cell carcinomas (HNSCC). Np63a, the most regulationAccumulating of RNA transcriptionevidence shows and that RNA epigenetic processing mechanisms [50]. predominantly expressed isoform in HNSCC, is over expressed are involved in the control of epidermal development and andRole sometimes of autophagy amplified in cutaneousin HNSCC tumors functions [41]. and TP63 terminal keratinocyte differentiation [51]. Multiple elements of First indication of autophagy in skin cells was produced almost thirty years ago showing the melanin macro globule (MMG), epigenetic machinery (e.g. DNMT1, JMJD3, SETD8, HDAC1 and 2, formerly called “macromelanosome,” a cytoplasmic spherical underlyingEHMT1 and epidermal 2, BRG1, CHD1, differentiation 3, and 4, BMI1, programs, CBX2, as4, andreviewed 6, EZH2, in granule formed in the melanocyte [42]. MMG are retained within JARID2, and SATB1) were implicated in molecular mechanisms melanocytes or transferred to keratinocytes and Langerhans cells number of genes involved in the control of nuclear/chromatin in the epidermis, and macrophages in the dermis, where they [51]. In the epidermis of p63-null mice the expression of a large can fuse with other heterolysosomes [41]. Cutaneous malignant wild-type controls [39]. On one hand, TP63 directly controls the melanomas often exhibit pigmented regions that are darker assembly and remodeling is significantly changed compared to than the surrounding skin [43]. While melanoma cells are the order chromatin structure in central domain of the epidermal original source of the melanin, keratinocytes and melanophages SATB1 transcription and promotes establishing of specific higher- also contribute to the tumor color because they contain melanin balance of gene expression during terminal keratinocyte obtained from melanoma cells [42]. Moreover, autophagy differentiation complex[39]. On required the other for hand,maintenance TP63 expressionof the proper in appears to be a common trait of invasive melanoma cells in the keratinocytes is regulated by histone methyltransferase SETD8, dermis [42]. Strikingly, the Caucasian skin keratinocytes exhibit which, in turn, is a target of c-Myc transcription factor and higher autophagic activity than those from African American skin mediates its effects on epidermal differentiation [52]. Another [42]. Melanosome accumulation in keratinocytes was accelerated by treatment with lysosomal inhibitors or with small interfering remodeling ATPase encoded by the HELLS gene, is essential for TP63 transcriptional target LSH, an SNF2-like chromatin essential for autophagy supporting its pivotal role in skin color determination,RNAs specific asfor well autophagy-related as in chemo- or proteins,immuno- therapeuticwhich are normal levels of DNA methylation and to drive skin stem cell treatment of melanoma patients [43-45]. proliferation and tumorigenesis [40]. LSH acts as an efficient TP63transcriptional was shown repressor to play a bycritical cooperating role in regulation with the of DNMT1,various epigeneticDNMT3B, HDAC1 enzymes and and HDAC2 accessory to silence proteins gene transcription by activating [40]. or UVB, a major cause of skin damage, which accompanies repressing their transcription, as well as modulating their levels showncomplex to alterationsinduce macroautophagy in irradiated andskin mitochondrial cells (e.g. DNA autophagy lesions, [46,47].oxidative Furthermore, stress, inflammation the epidermal and caspase expression activation), of SQSTM1, was also the TP63by TP63-dependent and microRNAs microRNAs in [53], skin Ratovitski, proliferation in preparation]. and differentiation psoriatic skin than in skin affected by atopic dermatitis or from healthykey regulator controls, of autophagy, suggesting isthe found role tofor be autophagy significantly in cutaneous higher in and migration of skin stem cells supported by the function induced autophagy in epidermal keratinocytes leading to of ArgonauteEssential role(AGO) of proteinsmicroRNAs as essentialin governing components a self-renewal of the ainflammation massive accumulation [48]. Both UVA- of andhigh-molecular-weight
Load more

Recommended publications
  • Synergistic Tumor Suppression by Combined Inhibition of Telomerase
    Synergistic tumor suppression by combined inhibition PNAS PLUS of telomerase and CDKN1A Romi Guptaa, Yuying Donga, Peter D. Solomona, Hiromi I. Wetterstenb, Christopher J. Chengc,d, JIn-Na Mina,e, Jeremy Hensonf,g, Shaillay Kumar Dograh, Sung H. Hwangi, Bruce D. Hammocki, Lihua J. Zhuj, Roger R. Reddelf,g, W. Mark Saltzmanc, Robert H. Weissb,k, Sandy Changa,e, Michael R. Greenl,1, and Narendra Wajapeyeea,1 Departments of aPathology and eLaboratory Medicine, Yale University School of Medicine, New Haven, CT 06510; iDepartment of Entomology and bDivision of Nephrology, Department of Internal Medicine, University of California, Davis, California 95616; Departments of cBiomedical Engineering and dMolecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511; fSydney Medical School, University of Sydney, NSW 2006, Australia; gCancer Research Unit, Children’s Medical Research Institute, Westmead, NSW 2145, Australia; hSingapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR), Brenner Center for Molecular Medicine, Singapore 117609; lHoward Hughes Medical Institute and jPrograms in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Massachusetts 01605; and kDepartment of Medicine, Mather VA Medical Center, Sacramento, CA 9565 Contributed by Michael R. Green, June 19, 2014 (sent for review June 8, 2014) Tumor suppressor p53 plays an important role in mediating growth dition to its role in cell cycle regulation, p21 has been shown in inhibition upon telomere dysfunction. Here, we show that loss of a variety of studies to repress apoptosis (9–13). the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, Here,westudytheroleofp21inthe context of telomerase in- also known as p21WAF1/CIP1) increases apoptosis induction following hibition.
    [Show full text]
  • Full Text (PDF)
    ResearchArticle DNA Damage–Dependent Translocation of B23 and p19ARF Is Regulated by the Jun N-Terminal Kinase Pathway Orli Yogev,1 Keren Saadon,1 Shira Anzi,1 Kazushi Inoue,2 and Eitan Shaulian1 1Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Jerusalem, Israel and 2Departments of Pathology/Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina Abstract arrest or apoptosis. However, increased tumor development in The dynamic behavior of the nucleolus plays a role in the triple knockout mice nullizygous for ARF, p53, and Mdm2 showed detection of and response to DNA damage of cells. Two that ARF acts also in a p53-independent manner (11). Some of the nucleolar proteins, p14ARF/p19ARF and B23, were shown to p53-independent activity is attributed to its ability to reduce rRNA translocate out of the nucleolus after exposure of cells to DNA- processing (12, 13) and inhibit oncogene-induced transcription damaging agents. This translocation affects multiple cellular (14, 15). functions, such as DNA repair, proliferation, and survival. In ARF augments p53 activity mainly in response to oncogenic this study, we identify a pathway and scrutinize the mecha- stress. Its expression is up-regulated in response to deregulated nisms leading to the translocation of these proteins after oncogenic activity due to elevated transcription governed by several transcription factors, such as E2F (16), c-myc (17), AP-1 exposure of cells to DNA-damaging agents. We show that redistribution of B23 and p19ARF after the exposure to (18), or by oncogenic Ras (19). A second mechanism regulating ARF activity involves the control of its subcellular localization (3).
    [Show full text]
  • P14ARF Inhibits Human Glioblastoma–Induced Angiogenesis by Upregulating the Expression of TIMP3
    P14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3 Abdessamad Zerrouqi, … , Daniel J. Brat, Erwin G. Van Meir J Clin Invest. 2012;122(4):1283-1295. https://doi.org/10.1172/JCI38596. Research Article Oncology Malignant gliomas are the most common and the most lethal primary brain tumors in adults. Among malignant gliomas, 60%–80% show loss of P14ARF tumor suppressor activity due to somatic alterations of the INK4A/ARF genetic locus. The tumor suppressor activity of P14ARF is in part a result of its ability to prevent the degradation of P53 by binding to and sequestering HDM2. However, the subsequent finding of P14ARF loss in conjunction with TP53 gene loss in some tumors suggests the protein may have other P53-independent tumor suppressor functions. Here, we report what we believe to be a novel tumor suppressor function for P14ARF as an inhibitor of tumor-induced angiogenesis. We found that P14ARF mediates antiangiogenic effects by upregulating expression of tissue inhibitor of metalloproteinase–3 (TIMP3) in a P53-independent fashion. Mechanistically, this regulation occurred at the gene transcription level and was controlled by HDM2-SP1 interplay, where P14ARF relieved a dominant negative interaction of HDM2 with SP1. P14ARF-induced expression of TIMP3 inhibited endothelial cell migration and vessel formation in response to angiogenic stimuli produced by cancer cells. The discovery of this angiogenesis regulatory pathway may provide new insights into P53-independent P14ARF tumor-suppressive mechanisms that have implications for the development of novel therapies directed at tumors and other diseases characterized by vascular pathology. Find the latest version: https://jci.me/38596/pdf Research article P14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3 Abdessamad Zerrouqi,1 Beata Pyrzynska,1,2 Maria Febbraio,3 Daniel J.
    [Show full text]
  • Loss of P21 Disrupts P14arf-Induced G1 Cell Cycle Arrest but Augments P14arf-Induced Apoptosis in Human Carcinoma Cells
    Oncogene (2005) 24, 4114–4128 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Loss of p21 disrupts p14ARF-induced G1 cell cycle arrest but augments p14ARF-induced apoptosis in human carcinoma cells Philipp G Hemmati1,3, Guillaume Normand1,3, Berlinda Verdoodt1, Clarissa von Haefen1, Anne Hasenja¨ ger1, DilekGu¨ ner1, Jana Wendt1, Bernd Do¨ rken1,2 and Peter T Daniel*,1,2 1Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charite´, Campus Berlin-Buch, Berlin-Buch, Germany; 2Max-Delbru¨ck-Center for Molecular Medicine, Berlin-Buch, Germany The human INK4a locus encodes two structurally p16INK4a and p14ARF (termed p19ARF in the mouse), latter unrelated tumor suppressor proteins, p16INK4a and p14ARF of which is transcribed in an Alternative Reading Frame (p19ARF in the mouse), which are frequently inactivated in from a separate exon 1b (Duro et al., 1995; Mao et al., human cancer. Both the proapoptotic and cell cycle- 1995; Quelle et al., 1995; Stone et al., 1995). P14ARF is regulatory functions of p14ARF were initially proposed to usually expressed at low levels, but rapid upregulation be strictly dependent on a functional p53/mdm-2 tumor of p14ARF is triggered by various stimuli, that is, suppressor pathway. However, a number of recent reports the expression of cellular or viral oncogenes including have implicated p53-independent mechanisms in the E2F-1, E1A, c-myc, ras, and v-abl (de Stanchina et al., regulation of cell cycle arrest and apoptosis induction by 1998; Palmero et al., 1998; Radfar et al., 1998; Zindy p14ARF. Here, we show that the G1 cell cycle arrest et al., 1998).
    [Show full text]
  • Alterations of P14arf, P53, and P73 Genes Involved in the E2F-1-Mediated Apoptotic Pathways in Non-Small Cell Lung Carcinoma
    [CANCER RESEARCH 61, 5636–5643, July 15, 2001] Alterations of p14ARF, p53, and p73 Genes Involved in the E2F-1-mediated Apoptotic Pathways in Non-Small Cell Lung Carcinoma Siobhan A. Nicholson,1 Nader T. Okby,1 Mohammed A. Khan, Judith A. Welsh, Mary G. McMenamin, William D. Travis, James R. Jett, Henry D. Tazelaar, Victor Trastek, Peter C. Pairolero, Paul G. Corn, James G. Herman, Lance A. Liotta, Neil E. Caporaso, and Curtis C. Harris2 Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 [S. A. N., M. A. K., J. A. W., M. G. M., L. A. L., N. E. C., C. C. H.]; Orange Pathology Associates, Middleton, New York 10940 [N. T. O.]; Armed Forces Institute of Pathology, Washington, DC 20306 [S. A. N., W. D. T.]; Mayo Clinic, Rochester, Minnesota 55905 [J. R. J., H. D. T., V. T., P. C. P.]; and The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [P. G. C., J. G. H.] ABSTRACT encoded by a separate exon 1␤ that lies ϳ20 kb upstream of exon 1␣ and shares exons 2 and 3 as read in an ARF, giving rise to a protein ARF Overexpression of E2F-1 induces apoptosis by both a p14 -p53- and INK4a ARF completely unrelated to p16 (14). Despite its unrelated structure, a p73-mediated pathway. p14 is the alternate tumor suppressor prod- ARF p14 also is capable of causing cell cycle arrest in G1 and G2. uct of the INK4a/ARF locus that is inactivated frequently in lung carci- ARF nogenesis. Because p14ARF stabilizes p53, it has been proposed that the loss p14 binds to and antagonizes the actions of MDM2, a negative of p14ARF is functionally equivalent to a p53 mutation.
    [Show full text]
  • Expression of P16 INK4A and P14 ARF in Hematological Malignancies
    Leukemia (1999) 13, 1760–1769 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu Expression of p16INK4A and p14ARF in hematological malignancies T Taniguchi1, N Chikatsu1, S Takahashi2, A Fujita3, K Uchimaru4, S Asano5, T Fujita1 and T Motokura1 1Fourth Department of Internal Medicine, University of Tokyo, School of Medicine; 2Division of Clinical Oncology, Cancer Chemotherapy Center, Cancer Institute Hospital; 3Department of Hematology, Showa General Hospital; 4Third Department of Internal Medicine, Teikyo University, School of Medicine; and 5Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan The INK4A/ARF locus yields two tumor suppressors, p16INK4A tumor suppressor genes.10,11 In human hematological malig- ARF and p14 , and is frequently deleted in human tumors. We nancies, their inactivation occurs mainly by means of homo- studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used zygous deletion or promoter region hypermethylation a quantitative reverse transcription-PCR assay. Normal periph- (reviewed in Ref. 12). In tumors such as pancreatic adenocar- eral bloods, bone marrow and lymph nodes expressed little or cinomas, esophageal squamous cell carcinomas and familial undetectable p16INK4A and p14ARF mRNAs, which were readily melanomas, p16INK4A is often inactivated by point mutation, detected in 12 and 17 of 41 cell lines, respectively. Patients with 12 INK4A which is not the case in hematological malignancies. On hematological malignancies frequently lacked p16 INK4C INK4D ARF the other hand, genetic aberrations of p18 or p19 expression (60/137) and lost p14 expression less frequently 12 (19/137, 13.9%).
    [Show full text]
  • Human P14arf-Mediated Cell Cycle Arrest Strictly Depends on Intact P53 Signaling Pathways
    Oncogene (2002) 21, 3207 ± 3212 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Human p14ARF-mediated cell cycle arrest strictly depends on intact p53 signaling pathways H Oliver Weber1,2, Temesgen Samuel1,3, Pia Rauch1 and Jens Oliver Funk*,1 1Laboratory of Molecular Tumor Biology, Department of Dermatology, University of Erlangen-Nuremberg, 91052 Erlangen, Germany; 2Regulation of Cell Growth Laboratory, National Cancer Institute, Frederick, Maryland, MD 21702-1201, USA The tumor suppressor ARF is transcribed from the INK4a/ 4 and 6 activities, thus leading to decreased phosphor- ARF locus in partly overlapping reading frames with the ylation of RB and to G1 arrest. Cells that are de®cient CDK inhibitor p16Ink4a. ARF is able to antagonize the for RB are resistant to p16Ink4a-mediated cell cycle MDM2-mediated ubiquitination and degradation of p53, arrest (Sherr and Roberts, 1995; Weinberg, 1995). leading to either cell cycle arrest or apoptosis, depending on ARF is also a cell cyle inhibitor. It does not directly the cellular context. However, recent data point to inhibit CDKs but interferes with the function of additional p53-independent functions of mouse p19ARF. MDM2 to destabilize p53. ARF may be activated by Little is known about the dependency of human p14ARF aberrant activation of oncoproteins such as Ras function on p53 and its downstream genes. Therefore, we (Palmero et al., 1998), c-myc (Zindy et al., 1998), analysed the mechanism of p14ARF-induced cell cycle arrest E1A (de Stanchina et al., 1998), Abl (Radfar et al., in several human cell types.
    [Show full text]
  • P14arf Expression Increases Dihydrofolate Reductase Degradation and Paradoxically Results in Resistance to Folate Antagonists in Cells with Nonfunctional P53
    [CANCER RESEARCH 64, 4338–4345, June 15, 2004] p14ARF Expression Increases Dihydrofolate Reductase Degradation and Paradoxically Results in Resistance to Folate Antagonists in Cells with Nonfunctional p53 Pellegrino G. Magro,1,2 Angelo J. Russo,1,2 Wei-Wei Li,2 Debabrata Banerjee,3 and Joseph R. Bertino3 1Joan and Sanford I. Weill Graduate School of Medical Sciences of Cornell University, New York, New York; 2Memorial Sloan Kettering Cancer Center, New York, New York; and 3The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey ABSTRACT Although much is known about the function of ARF in the p53 pathway, less is known about its functions in human tumor growth and ARF The p14 protein, the product of an alternate reading frame of the chemosensitivity independently of its regulation of p53 via binding to INK4A/ARF locus on human chromosome 9p21, disrupts the ability of MDM2. Mouse embryonic fibroblasts expressing E1A and exogenous MDM2 to target p53 for proteosomal degradation and causes an increase ARF are more sensitive to killing by doxorubicin than their normal in steady-state p53 levels, leading to a G1 and G2 arrest of cells in the cell cycle. Although much is known about the function of p14ARF in the p53 counterparts that only express E1A (7). Alterations in the INK4A/ pathway, not as much is known about its function in human tumor growth ARF locus reduce p53 induction and cytotoxicity of cyclophospha- and chemosensitivity independently of up-regulation of p53 protein levels. mide in mouse lymphomas (16). Also, recombinant adenovirus-me- To learn more about its effect on cellular proliferation and chemoresis- diated p14ARF overexpression sensitizes MCF-7 breast cancer cells to tance independent of p53 up-regulation, human HT-1080 fibrosarcoma cisplatin (17).
    [Show full text]
  • Differential Roles of P16 and P14 Genes in Prognosis of Oral
    414 Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma R. Sailasree,1 A. Abhilash,1 K.M. Sathyan,1 K.R. Nalinakumari,2 Shaji Thomas,3 and S. Kannan1 1Laboratory of Cell Cycle Regulation and Molecular Oncology, Division of Cancer Research, 2Division of Dental Surgery, and 3Division of Surgical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India Abstract INK4A Background: Oral cancer patients are found to have observed in 30% of the cases. p16 deletion was poor clinical outcome and high disease recurrence associated with aggressive tumors, as evidenced by the rate, in spite of an aggressive treatment regimen. The nodal involvement of the disease. Low or absence of inactivation of INK4A/ARF loci is reported to be second p16INK4A protein adversely affected the initial treat- INK4A to p53 inactivation in human cancers. The purpose of ment response. Promoter methylation of p16 was this study was to assess the prognostic significance of associated with increased disease recurrence and acts the molecular aberrations in the INK4A locus for as an independent predictor for worse prognosis. ARF effective identification of aggressive oral carcinoma Surprisingly, p14 methylation associated with cases needing alternate therapy. lower recurrence rate in oral cancer patients with a Materials and Methods: The study composed of 116 good clinical outcome. Overall survival of these patients freshly diagnosed with oral carcinoma. The patients was associated with tumor size, nodal disease, INK4A genetic and epigenetic status of the p16 and and p16INK4A protein expression pattern. Our results ARF INK4A ARF p14 genes was evaluated. The relation between indicate that p16 and p14 alterations constitute these genic alterations and different treatment end a major molecular abnormality in oral cancer cases.
    [Show full text]
  • ARF Promotes Accumulation of Retinoblastoma Protein Through Inhibition of MDM2
    Oncogene (2007) 26, 4627–4634 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2 DLF Chang1, W Qiu1, H Ying2, Y Zhang3, C-Y Chen4 and Z-XJ Xiao1,2 1Graduate Program in Molecular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 2Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; 3The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA and 4Department of Pathology, Boston University School of Medicine, Boston, MA, USA The INK4a/ARF locus,encoding two tumor suppressor binds to and inhibits cyclin D-associated kinases proteins,p16 INK4a and p14ARF (ARF),plays key roles in resulting in hypophosphorylated retinoblastoma protein many cellular processes including cell proliferation, (Rb), a biologically active Rb species in tumor suppres- apoptosis,cellular senescence and differentiation. Inacti- sion (Weinberg, 1995). It was later discovered that the vation of INK4a/ARF is one of the most frequent events same locus encodes a second protein through the usage during human cancer development. Although p16INK4a is of a separate promoter with a distinct first exon (exon a critical component in retinoblastoma protein (Rb)- 1b), which results in translation from an alternate mediated growth regulatory pathway,p14 ARF plays a reading frame (ARF) encoding a basic, nucleolar pivotal role in the activation of p53 upon oncogenic stress protein named p14ARF in human (p19ARF in mouse). signals. A body of evidence indicates that ARF also ARF shares no amino acid homology with p16INK4a possesses growth suppression functions independent of protein and is activated by oncogenic stress signals, such p53,the mechanism of which is not well understood.
    [Show full text]
  • Regulation of the P53 Family Proteins by the Ubiquitin Proteasomal Pathway
    International Journal of Molecular Sciences Review Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway Scott Bang, Sandeep Kaur and Manabu Kurokawa * Department of Biological Sciences, Kent State University, Kent, OH 44242, USA; [email protected] (S.B.); [email protected] (S.K.) * Correspondence: [email protected]; Tel.: +1-330-672-2979 Received: 27 November 2019; Accepted: 24 December 2019; Published: 30 December 2019 Abstract: The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions. Keywords: apoptosis; cancer; Tp53; Tp63; Tp73; ubiquitination; E3 ligase 1. Introduction The “guardian of the genome”, p53, has long been known to regulate the cellular responses of DNA repair, cell senescence, cell cycle arrest, and apoptosis [1]. Mice deficient in p53 exhibit significantly increased susceptibility to tumor formation compared to wild type mice and are a valuable tool with which to study the effects of p53 on tumor initiation and progression [2].
    [Show full text]
  • An Epigenetically Derived Monoclonal Origin for Recurrent Respiratory Papillomatosis
    ORIGINAL ARTICLE An Epigenetically Derived Monoclonal Origin for Recurrent Respiratory Papillomatosis Josena Kunjoonju Stephen, MD; Lori E. Vaught, MD; Kang Mei Chen, MD; Veena Shah, MD; Vanessa G. Schweitzer, MD; Glendon Gardner, MD; Michael S. Benninger, MD; Maria J. Worsham, PhD Objective: To investigate the contribution of pro- cer genes in the multigene panel had altered DNA meth- moter methylation-mediated epigenetic events in recur- ylation in at least 1 laryngeal papilloma biopsy speci- rent respiratory papillomatosis tumorigenesis. men. Identical abnormally methylated genes were found in 5 of 15 recurrent cases, of which the CDKN2B gene Design: Archival tissue DNA, extracted from microdis- was hypermethylated in all 5 cases. Dissimilar epige- sected papilloma lesions, was interrogated for methyl- netic events were noted in the remaining cases. ation status by means of the novel, multigene methylation- specific multiplex ligation-dependent probe amplification Conclusions: A clonal origin was derived for 5 of 15 assay. recurrent respiratory papillomatosis biopsy specimens based on identical epigenetic events. The high fre- Subjects: Fifteen subjects with recurrent respiratory pap- quency of epigenetic events, characterized by consis- illomatosis, 3 females and 12 males, all with adult onset tent promoter hypermethylation of multiple tumor of illness (age range, 23-73 years) except for 1 female pa- suppressor genes, points to the use of gene silencing tient with juvenile onset (1 year old). mechanisms in the pathogenesis of recurrent respira- tory papillomatosis. Results: Promoter hypermethylation was recorded in 14 of 15 cases, and 19 of 22 unique methylation-prone can- Arch Otolaryngol Head Neck Surg. 2007;133(7):684-692 ECURRENT RESPIRATORY small percentage of RRP cases progress to (laryngeal) papillomatosis malignancy.9 (RRP), an extremely rare Laryngeal papillomas usually run a be- condition, is characterized nign but recurrent course.
    [Show full text]