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Alea A. Mills - One of the best experts on this subject based on the ideXlab platform.

  • TAP63 induces senescence and suppresses tumorigenesis in vivo
    Nature Cell Biology, 2009
    Co-Authors: William M Keyes, Scott W. Lowe, Hannes Vogel, Cristian Papazoglu, Johannes Zuber, Wangzhi Li, Alea A. Mills
    Abstract:

    P63 is distinct from its homologue p53 in that its role as a tumour suppressor is controversial, an issue complicated by the existence of two classes of P63 isoforms^ 1 . Here we show that TAP63 isoforms are robust mediators of senescence that inhibit tumorigenesis in vivo . Whereas gain of TAP63 induces senescence, loss of P63 enhances sarcoma development in mice lacking p53. Using a new TAP63-specific conditional mouse model, we demonstrate that TAP63 isoforms are essential for Ras-induced senescence, and that TAP63 deficiency increases proliferation and enhances Ras-mediated oncogenesis in the context of p53 deficiency in vivo . TAP63 induces senescence independently of p53, p19^Arf and p16^Ink4a, but requires p21^Waf/Cip1 and Rb. TAP63-mediated senescence overrides Ras-driven transformation of p53-deficient cells, preventing tumour initiation, and doxycycline-regulated expression of TAP63 activates p21^Waf/Cip1, induces senescence and inhibits progression of established tumours in vivo . Our findings demonstrate that TAP63 isoforms function as tumour suppressors by regulating senescence through p53-independent pathways. The ability of TAP63 to trigger senescence and halt tumorigenesis irrespective of p53 status identifies TAP63 as a potential target of anti-cancer therapy for human malignancies with compromised p53. TAP63, a splice variant of the p53 homologue P63, suppresses tumorigenesis in p53-null mice by mediating Ras oncogene-induced senescence. TAP63-mediated senescence is independent of p53, but requires p21Waf/Cip1 and Rb. TAP63 overrides Ras-driven transformation, while its loss accelerates Ras oncogenesis.

  • P63, cellular senescence and tumor development.
    Cell Cycle, 2007
    Co-Authors: Xuecui Guo, Alea A. Mills
    Abstract:

    Deficiency of P63, a p53-related protein, causes severe defects in epithelial morphogenesis. Studies of P63 compromised mouse models reveal that P63 deficiency induces cellular senescence both in cultured cells and in vivo, through regulation p19Arf/p53 and p16Ink4a/Rb pathways. An extensive tumor study of P63-compromised mice demonstrated that P63 deficiency does not predispose to, but rather protects from, tumor development. These findings further implicate P63 as a negative regulator of the tumor suppressive mechanism of cellular senescence.

  • P63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation
    Development, 2006
    Co-Authors: Johanna Laurikkala, Alea A. Mills, Marja L Mikkola, Martyn J James, Mark Tummers, Irma Thesleff
    Abstract:

    Heterozygous germline mutations in P63 , a transcription factor of the p53 family, result in abnormal morphogenesis of the skin and its associated structures, including hair follicles and teeth. In mice lacking P63 , all ectodermal organs fail to develop, and stratification of the epidermis is absent. We show that the ectodermal placodes that mark early tooth and hair follicle morphogenesis do not form in P63 -deficient embryos, although the multilayered dental lamina that precedes tooth placode formation develops normally. The N-terminally truncated isoform of P63 (ΔNP63) was expressed at high levels in embryonic ectoderm at all stages of tooth and hair development, and it was already dominant over the transactivating TAP63 isoform prior to epidermal stratification. Bmp7, Fgfr2b, Jag1 and Notch1 transcripts were co-expressed withΔ NP63 in wild-type embryos, but were not detectable in the ectoderm of P63 mutants. In addition, β-catenin and Edar transcripts were significantly reduced in skin ectoderm. We also demonstrate that BMP2, BMP7 and FGF10 are potent inducers of P63 in cultured tissue explants. Hence, we suggest that P63 regulates the morphogenesis of surface ectoderm and its derivatives via multiple signalling pathways.

  • P63: oncogene or tumor suppressor?
    Current opinion in genetics & development, 2005
    Co-Authors: Alea A. Mills
    Abstract:

    p53, the original member of the family of genes now known to include P63 and p73, was first heralded as an oncogene because of its potent transformation capabilities and its robust expression in human tumors. However, it was later discovered that only mutant p53 was oncogenic, and that wild type p53 functioned as a tumor suppressor. Decades later, P63, the newest member of this gene family, is involved in a similar controversy: is P63 an oncogene or a tumor suppressor? Recent progress on understanding the in vivo role of P63 in cancer has focused primarily on investigating its involvement in the tumor-suppressive mechanism of apoptosis, by analyzing mouse models to assess its tumor-suppressive capabilities, and by assessing its expression in human cancers.

  • P63 is an essential proapoptotic protein during neural development
    Neuron, 2005
    Co-Authors: Bradley W Jacobs, William M Keyes, Alea A. Mills, Gregory Govoni, Daniel Ho, Jasvinder K Atwal, Fanie Barnabeheider, Freda D Miller
    Abstract:

    Summary The p53 family member P63 is required for nonneural development, but has no known role in the nervous system. Here, we define an essential proapoptotic role for P63 during naturally occurring neuronal death. Sympathetic neurons express full-length TAP63 during the developmental death period, and TAP63 levels increase following NGF withdrawal. Overexpression of TAP63 causes neuronal apoptosis in the presence of NGF, while cultured P63 −/− neurons are resistant to apoptosis following NGF withdrawal. TAP63 is also essential in vivo, since embryonic P63 −/− mice display a deficit in naturally occurring sympathetic neuron death. While both TAP63 and p53 induce similar apoptotic signaling proteins and require BAX expression and function for their effects, TAP63 induces neuronal death in the absence of p53, but p53 requires coincident P63 expression for its proapoptotic actions. Thus, P63 is essential for developmental neuronal death, likely functioning both on its own, and as an obligate proapoptotic partner for p53.

Gerry Melino - One of the best experts on this subject based on the ideXlab platform.

  • P63 and p73, the Ancestors of p53
    Cold Spring Harbor perspectives in biology, 2010
    Co-Authors: Volker Dötsch, D Coutandin, Francesca Bernassola, Eleonora Candi, Gerry Melino
    Abstract:

    p73 and P63 are two homologs of the tumor suppressive transcription factor p53. Given the high degree of structural similarity shared by the p53 family members, p73 and P63 can bind and activate transcription from the majority of the p53-responsive promoters. Besides overlapping functions shared with p53 (i.e., induction of apoptosis in response to cellular stress), the existence of extensive structural variability within the family determines unique roles for P63 and p73. Their crucial and specific functions in controlling development and differentiation are well exemplified by the P63 and p73 knockout mouse phenotypes. Here, we describe the contribution of P63 and p73 to human pathology with emphasis on their roles in tumorigenesis and development.

  • the promyelocytic leukaemia protein tumour suppressor functions as a transcriptional regulator of P63
    Oncogene, 2005
    Co-Authors: Gerry Melino, Francesca Bernassola, Andrew Oberst, Pier Paolo Pandolfi
    Abstract:

    P63 plays unique developmental roles in epidermal morphogenesis, despite its structural similarity with p53. The P63 gene has two distinct promoters, coding for proteins containing an N-terminal transactivation domain (TA isoforms) and for proteins lacking this region (AN isoforms). The full-length transcriptionally active TAP63 isoforms are capable of transactivating the majority of the p53 target promoters thus inducing cell cycle arrest and apoptosis. On the contrary, the ANP63 isoforms seem to counteract the transactivation activities of p53 and TAP63 proteins, thus possibly conferring a proliferative advantage to cancer cells. However, the molecular mechanisms controlling the transcriptional activity of P63 remain largely unclear. Here we present data indicating that (i) the promyelocytic leukaemia protein (PML) physically interacts with P63, (ii) P63 is localized into the PML nuclear-bodies (PML-NBs) in vivo, and (iii) PML regulates P63 transcriptional activity. We show that the interaction of P63 with PML increases the levels of P63 in cultured cells as well as its ability to transactivate the p53-responsive elements of the GADD45, p21 and bax promoters. These data are consistent with a general role for PML as a functional modulator of all the p53 family members. Our findings strengthen the relevance of the cross talk between PML and the p53 family members, imply a new tumour suppressive function of PML and unveil a possible role for PML in epidermal morphogenesis and differentiation.

  • Functional regulation of p73 and P63: development and cancer
    Trends in Biochemical Sciences, 2003
    Co-Authors: Gerry Melino, Xin Lu, Milena Gasco, Tim Crook, Richard A. Knight
    Abstract:

    The transcription factor and tumour suppressor p53 and its two homologues P63 and p73 form a family of proteins. P63 and p73 show much greater molecular complexity than p53 because they are expressed both as multiple alternatively spliced C-terminal isoforms, and as N-terminally deleted, dominant-negative proteins that show reciprocal functional regulation. In addition, several other factors, such as post-translational modifications and specific and common family regulatory proteins, result overall in subtle modulation of their biological effects. Although all p53, P63 and p73 family members are regulators of the cell cycle and apoptosis, the developmental abnormalities of p73- and P63-null mice do not show enhanced tumour susceptibility of p53 knockouts, suggesting that complex regulatory processes modulate the functional effects of this family of proteins.

  • the p53 P63 p73 family of transcription factors overlapping and distinct functions
    Journal of Cell Science, 2000
    Co-Authors: Massimo Levrero, V De Laurenzi, Antonio Costanzo, J Gong, J Y Wang, Gerry Melino
    Abstract:

    The p53 gene is the most frequently mutated gene in human cancer. The identification of two homologues, P63 and p73, revealed that p53 is a member of a family of related transcription factors. Given that they share amino acid sequence identity reaching 63% in the DNA-binding domain, p53, P63 and p73 should have redundant functions in the regulation of gene expression. Indeed, p73 can activate p53-regulated genes and suppress growth or induce apoptosis. Moreover, p53 and p73 are both induced by DNA damage - albeit through distinct mechanisms. Other evidence, however, suggests that P63 and p73 are important for regulation of normal development. An extended C-terminal region, not found in p53, is alternatively spliced in P63 and p73. Within this C-terminal extension is a sterile α motif (SAM) previously found in other proteins that regulate development. The P63-deficient mice showed developmental abnormalities. Interestingly, the human P63 gene is mutated in children who have the disease Ectrodactyly, Ectodermal dysplasia and facial Clefts (EEC) syndrome, and the disease phenotype is similar to the one of P63-deficient mice. The P63 and p73 genes are rarely mutated in human cancer, although p73 loss is observed in neuroblastoma and a subtype of T-cell lymphoma. p53, P63 and p73 appear to have overlapping and distinct functions: p53 regulates the stress response to suppress tumors; P63 is essential for ectoderm development; and p73 might regulate both the stress response and development. Because p53 and p73 are linked to different upstream pathways, this family of transcription factors might regulate a common set of genes in response to different extracellular signals and developmental cues.

Vincenza Guzzardo - One of the best experts on this subject based on the ideXlab platform.

  • a mutant p53 smad complex opposes P63 to empower tgfβ induced metastasis
    Cell, 2009
    Co-Authors: Maddalena Adorno, Michelangelo Cordenonsi, Marco Montagner, Sirio Dupont, Christine Wong, Byron Hann, Aldo Solari, Sara Bobisse, Maria Rondina, Vincenza Guzzardo
    Abstract:

    TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by P63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/P63 protein complex in which Smads serve as essential platforms. Within this ternary complex, P63 functions are antagonized. Downstream of P63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of P63 function.

  • a mutant p53 smad complex opposes P63 to empower tgfβ induced metastasis
    Cell, 2009
    Co-Authors: Maddalena Adorno, Michelangelo Cordenonsi, Marco Montagner, Sirio Dupont, Christine Wong, Byron Hann, Aldo Solari, Sara Bobisse, Maria Rondina, Vincenza Guzzardo
    Abstract:

    Summary TGFβ ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFβ-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by P63. Mechanistically, TGFβ acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/P63 protein complex in which Smads serve as essential platforms. Within this ternary complex, P63 functions are antagonized. Downstream of P63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFβ-dependent inhibition of P63 function.

Frank Mckeon - One of the best experts on this subject based on the ideXlab platform.

  • tumor predisposition in mice mutant for P63 and p73 evidence for broader tumor suppressor functions for the p53 family
    Cancer Cell, 2005
    Co-Authors: Elsa R Flores, Denise Crowley, Shomit Sengupta, Annie Yang, John B Miller, Jamie J Newman, Roderick T Bronson, Frank Mckeon
    Abstract:

    Summary P63 and p73 are functionally and structurally related to the tumor suppressor p53 . However, their own role in tumor suppression is unclear. Given the p53 -like properties of P63 and p73 , we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that P63 +/− ; p73 +/− mice develop spontaneous tumors. Loss of P63 and p73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and P63 or p53 and p73 displayed higher tumor burden and metastasis compared to p53 +/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported.

  • loss of P63 expression is associated with tumor progression in bladder cancer
    American Journal of Pathology, 2002
    Co-Authors: Marshall J Urist, Frank Mckeon, Charles J Di Como, Elizabeth Charytonowicz, David Verbel, Christopher P Crum, Tan A Ince, Carlos Cordoncardo
    Abstract:

    P63, a member of the p53 gene family, encodes multiple proteins that may either transactivate p53 responsive genes (TAP63) or act as a dominant-negative factor toward p53 and p73 (ΔNP63). P63 is expressed in many epithelial compartments and P63−/− mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that P63 is expressed in normal urothelium. This study reports that P63 is regulated in bladder carcinogenesis and that P63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain P63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of ΔNP63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that P63−/− mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, P63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium.

  • P63 and p73 are required for p53 dependent apoptosis in response to dna damage
    Nature, 2002
    Co-Authors: Elsa R Flores, Kenneth Y Tsai, Denise Crowley, Shomit Sengupta, Annie Yang, Frank Mckeon, Tyler Jacks
    Abstract:

    The tumour-suppressor gene p53 is frequently mutated in human cancers and is important in the cellular response to DNA damage1,2. Although the p53 family members P63 and p73 are structurally related to p53, they have not been directly linked to tumour suppression, although they have been implicated in apoptosis3,4,5,6,7,8,9. Given the similarity between this family of genes and the ability of P63 and p73 to transactivate p53 target genes10,11, we explore here their role in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for one or a combination of p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene12,13,14. While using the E1A system facilitated our ability to perform biochemical analyses, we also examined the functions of P63 and p73 using an in vivo system in which apoptosis has been shown to be dependent on p53. Using both systems, we show here that the combined loss of P63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage.

  • P63 is a prostate basal cell marker and is required for prostate development
    American Journal of Pathology, 2000
    Co-Authors: Annie Yang, Sabina Signoretti, David Waltregny, James R Dilks, Beth Isaac, Douglas I Lin, Levi A Garraway, Rondolfo Montironi, Frank Mckeon
    Abstract:

    The p53 homologue P63 encodes for different isotypes able to either transactivate p53 reporter genes ( TAP63 ) or act as p53 -dominant-negatives ( ΔNP63 ). P63 is expressed in the basal cells of many epithelial organs and its germline inactivation in the mouse results in agenesis of organs such as skin appendages and the breast. Here, we show that prostate basal cells, but not secretory or neuroendocrine cells, express P63. In addition, prostate basal cells in culture predominantly express the ΔNP63α isotype. In contrast, P63 protein is not detected in human prostate adenocarcinomas. Finally, and most importantly, P63 (−/−) mice do not develop the prostate. These results indicate that P63 is required for prostate development and support the hypothesis that basal cells represent and/or include prostate stem cells. Furthermore, our results show that P63 immunohistochemistry may be a valuable tool in the differential diagnosis of benign versus malignant prostatic lesions.

Joost Schalkwijk - One of the best experts on this subject based on the ideXlab platform.

  • apr 246 prima 1 met rescues epidermal differentiation in skin keratinocytes derived from eec syndrome patients with P63 mutations
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Jinfeng Shen, Evelyn N Kouwenhoven, Vladimir J N Bykov, Tuula Rinne, Geuranne S Tjabringa, Christian Gilissen, Simon J Van Heeringen, Ellen H Van Den Bogaard, Joost Schalkwijk
    Abstract:

    p53 and P63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in P63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with P63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1MET (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of P63 target-gene expression. Our data show that EEC patient keratinocytes with P63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant P63-associated developmental abnormalities.

  • APR-246/PRIMA-1 MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with P63 mutations
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Jinfeng Shen, Evelyn N Kouwenhoven, Vladimir J N Bykov, Tuula Rinne, Geuranne S Tjabringa, Christian Gilissen, Simon J Van Heeringen, Ellen H Van Den Bogaard, Joost Schalkwijk
    Abstract:

    p53 and P63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in P63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with P63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1MET (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of P63 target-gene expression. Our data show that EEC patient keratinocytes with P63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant P63-associated developmental abnormalities.