Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medulloblastoma is a malignant tumor that arises in the cerebellum in children, presumably by transformation of granule neuron precursor cells. In vivo models of medulloblastoma in genetically engineered mice have shown that activation of signal transduction pathways that stimulate proliferation and inhibit differentiation of neural progenitor cells during cerebellar development initiate medulloblastoma formation. Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shh-mediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma. By revealing which cell signaling proteins can initiate medulloblastoma formation, mouse models have enabled investigators to identify molecular targets for designing new therapies. Small-molecule inhibitors of the Shh/Patched and PI3K pathways are potential chemotherapeutic agents for patients with medulloblastoma.
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PMID:Modeling medulloblastoma with genetically engineered mice. 1639 71

Urothelial carcinoma (UC), the common histological subtype of bladder cancer, presents as a papillary tumor or as an invasive, often lethal form. To study UC molecular biology, candidate gene and genome-wide approaches have been followed. Here, it is argued that a 'cancer pathway' perspective is useful to integrate findings from both approaches. According to this view, papillary cancers typically exhibit activation of the MAPK pathway, as a consequence of oncogenic mutations in FGFR3 or HRAS, with increased Cyclin D1 expression. In contrast, invasive UC are characterized by severe disturbances in proximate cell cycle regulators, e.g. RB1 and CDKN2A/p16(INK4A), which decrease dependency on mitogenic signaling. In addition, these disturbances permit, promote and are in turn exacerbated by chromosomal instability, which is further enhanced by loss of TP53 function. In another vicious cycle, defective cell cycle regulation interacts with DNA methylation alterations. The transition toward invasive UC may require concomitant and interacting defects in cell cycle regulation and the control of genomic stability. Intriguingly, neither canonical WNT/beta-Catenin nor hedgehog signaling appear to play major roles in UC. This may reflect its origin from more differentiated urothelial cells possessing a high regenerative potential rather than a stem cell population.
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PMID:Understanding urothelial carcinoma through cancer pathways. 1655 69

Development of skin appendages such as teeth, hairs and many exocrine glands, is regulated by inductive interactions between epithelial and mesenchymal tissues. At the molecular level, this interplay is mediated by conserved signaling proteins of the Wnt, FGF, TGFbeta, hedgehog and TNF families and executed by their downstream transcriptional regulators. p63, a transcription factor of the p53 family, is essential for the development of epidermis and its derivatives in vertebrates. The genomic organization of p63 is complex leading to transcription of at least six different isoforms with different, possibly even opposite functions. In humans, dominantly inherited mutations in p63 lead to a plenitude of syndromes that are featured by ectodermal dysplasia and/or craniofacial and limb malformations. In mice, lack of p63 causes a striking phenotype including severely truncated limbs, and absence of stratified epithelia and skin derivatives including teeth, hair follicles and mammary, lacrimal and salivary glands. While the significance of p63 for the morphogenesis of skin appendages is obvious, the molecular pathways regulated by p63 are only now emerging. This review discusses the current knowledge on the role of p63 in skin appendage development with emphasis on teeth and hair follicles.
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PMID:p63 in skin appendage development. 1726 78

Sessile serrated adenomas and traditional serrated adenomas are pathogenetically related to inhibition of apoptosis. Survivin and hedgehog proteins, including sonic hedgehog, patched, and smoothened, inhibit apoptosis, with hedgehog proteins forming a signal transduction cascade implicated in digestive cancers. This study compares survivin and hedgehog protein expression in serrated polyps and tubulovillous adenomas. Biopsies of sessile serrated adenomas (48) and traditional serrated adenomas (10) diagnosed during 2005 were retrieved from our files. Biopsies of normal mucosa (10), hyperplastic polyps (14), and tubulovillous adenomas (22) were used for comparison. Immunohistochemistry for survivin, sonic hedgehog, patched, and smoothened was graded as high or low grade. chi(2) tests were used to evaluate correlation between polyp type and survivin and hedgehog expression. Traditional serrated adenomas were also compared to sessile serrated adenomas with foci of cytological dysplasia (11 cases) with respect to MLH1 and p53 expression. Sessile serrated adenomas showed high-grade nuclear and cytoplasmic expression of survivin at the bottom of crypts more frequently than tubulovillous adenomas (60% versus 18%, P = .001 [nuclear]; 54% versus 18%, P = .005 [cytoplasm]), the latter showing a top-heavy pattern of staining. Survivin expression in hyperplastic polyps was similar to sessile serrated adenomas, being bottom-heavy, whereas traditional serrated adenomas showed diffuse staining throughout crypts. Although traditional serrated adenomas showed high-grade expression of sonic hedgehog more frequently than tubulovillous adenomas (90% versus 18%; P < .001), sonic hedgehog, patched, and smoothened expression was low grade among normal mucosa, hyperplastic polyps, and sessile serrated adenomas. All cytological dysplasias showed increased p53 expression within dysplastic foci, and MLH1 was also lost within dysplastic foci in 4 cases; traditional serrated adenomas showed intact MLH1 expression and minimal p53 expression throughout. Survivin expression is localized to the bottom of crypts in sessile serrated adenomas and hyperplastic polyps, whereas tubulovillous adenomas show top-heavy expression. Traditional serrated adenomas express survivin throughout crypts, suggesting intersection between the serrated and conventional adenoma-cancer pathways. Sonic hedgehog up-regulation is characteristic of traditional serrated adenomas, distinguishing this entity from other colorectal polyps.
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PMID:Survivin and hedgehog protein expression in serrated colorectal polyps: an immunohistochemical study. 1739 30

The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.
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PMID:Loss of suppressor-of-fused function promotes tumorigenesis. 1745 75

Skin undergoes self-renewal throughout life. Terminally differentiated keratinocytes, namely the corneocytes, are continually shed from the surface of the skin, whereas immature cells produce progeny that proceed through the differentiation process. Notch signaling controls a number of cellular processes including cell fate decision, proliferation, differentiation and survival/apoptosis. Hence, Notch and its ligands are expressed in multiple tissues including the skin, where they are abundantly expressed in the epidermis. Notch activation results in the promotion of growth arrest and the onset of differentiation, therefore suggesting that specific Notch activation may regulate skin homeostasis by balancing these processes, i.e. Notch signaling functions as a molecular switch that controls the transition of cells between skin layers during the epidermal differentiation process. Recent advances in the study of Notch signaling have confirmed that there is cross-talk between the Notch signaling pathway and a variety of other signaling molecules including Sonic hedgehog (Shh), beta-catenin and the p53 family member, p63. The absence of Notch activity allows Wnt and Shh signaling to persist in a tissue where they are normally repressed. In addition, Notch counteracts the action of p63 to maintain immature cell characteristics. However, aberrant Notch signaling results in the development of psoriasis and skin cancers such as squamous cell carcinoma, basal cell carcinoma and malignant melanoma. Future efforts to further define how Notch controls cell proliferation and differentiation may lead to the application of Notch in new therapies for various skin diseases.
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PMID:Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. 1762 39

Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.
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PMID:Essential role of stromally induced hedgehog signaling in B-cell malignancies. 1763 27

The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth. This summary of the Tumour Suppressors in Liver Carcinogenesis Symposium held at the 2007 EASL Annual Meeting discusses four pathways with pre-eminent tumour suppressor activity, each involved in hepatocarcinogenesis: p53, mTOR, beta-catenin and hedgehog.
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PMID:Tumour suppressors in liver carcinogenesis. 1793 20

Hedgehog-mediated signaling has been shown to promote growth and dissemination of solid cancers, most prominently basal cell carcinomas and medulloblastoma. Recent findings indicate that hedgehog signals are also important for tumor growth in hematologic malignancies. Hedgehog ligands secreted by stromal cells could elicit Patched/Smoothened-mediated antiapoptotic signaling in mouse B-cell lymphomas. Inhibition of hedgehog signaling induced apoptosis in lymphoma cells and prolonged survival of lymphoma-bearing mice. Depletion of tumor cells proceeded in the absence of p53 via the mitochondrial apoptotic pathway. These and other recently published data on hedgehog inhibition in cancer cells and their implications will be discussed.
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PMID:Stroma-initiated hedgehog signaling takes center stage in B-cell lymphoma. 1828 68

Skin cancers, i.e., basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma, belong to the most frequent tumors. Their formation is based on constitutional and/or inherited factors usually combined with environmental factors, mainly UV-irradiation through long term sun exposure. UV-light can randomly induce DNA damage in keratinocytes, but it can also mutate genes essential for control and surveillance in the skin epidermis. Various repair and safety mechanisms exist to maintain the integrity of the skin epidermis. For example, UV-light damaged DNA is repaired and if this is not possible, the DNA damaged cells are eliminated by apoptosis (sunburn cells). This occurs under the control of the p53 suppressor gene. Fas-ligand (FasL), a member of the tumor necrosis superfamily, which is preferentially expressed in the basal layer of the skin epidermis, is a key surveillance molecule involved in the elimination of sunburn cells, but also in the prevention of cell transformation. However, UV light exposure downregulates FasL expression in keratinocytes and melanocytes leading to the loss of its sensor function. This increases the risk that transformed cells are not eliminated anymore. Moreover, important control and surveillance genes can also be directly affected by UV-light. Mutation in the p53 gene is the starting point for the formation of SCC and some forms of BCC. Other BCCs originate through UV light mediated mutations of genes of the hedgehog signaling pathway which are essential for the maintainance of cell growth and differentiation. The transcription factor Gli2 plays a key role within this pathway, indeed, Gli2 is responsible for the marked apoptosis resistance of the BCCs. The formation of malignant melanoma is very complex. Melanocytes form nevi and from the nevi melanoma can develop through mutations in various genes. Once the keratinocytes or melanocytes have been transformed they re-express FasL which may allow the expanding tumor to evade the attack of immune effector cells. FasL which is involved in immune evasion or genes which govern the apoptosis resistance, e.g., Gli2 could therefore be prime targets to prevent tumor formation and growth. Attempts to silence these genes by RNA interference using gene specific short interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) have been functionally successful not only in tissue cultures and tumor tissues, but also in a mouse model. Thus, siRNAs and/or shRNAs may become a novel and promising approach to treat skin cancers at an early stage.
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PMID:Apoptosis and pathogenesis of melanoma and nonmelanoma skin cancer. 1834 64


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