Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperpigmentation of the skin is characterized by increases in melanin synthesis and deposition. Although considered a significant psychosocial distress, little is known about the detailed mechanisms of hyperpigmentation. Recently, the tumor suppressor protein p53 has been demonstrated to promote ultraviolet B-induced skin pigmentation by stimulating the transcription of a melanogenic cytokine, POMC (pro-opiomelanocortin), in keratinocytes. Given that p53 can be activated by various kinds of diverse stresses, including sun exposure, inflammation, and aging, this finding led us to examine the involvement of p53 in cytokine receptor signaling, which might result in skin hyperpigmentation. Immunohistochemical and reverse transcription-PCR analyses revealed the increased expression and phosphorylation of p53 in the epidermis of hyperpigmented spots, accompanied by the higher expression of melanogenic cytokines, including stem cell factor, endothelin-1, and POMC. The involvement of p53 in hyperpigmentation was also indicated by the significantly higher expression of p53 transcriptional targets in the epidermis of hyperpigmented spots. Treatment of human keratinocytes and melanocytes with known p53 activators or inhibitors, including pifithrin-alpha (PFT), demonstrated significant increases or decreases, respectively, in the expression of melanogenic factors, including cytokines and their receptors. Additionally, PFT administration abolished stem cell factor-induced phosphorylation of mitogen-activated protein kinase in human melanocytes. Furthermore, when organ-cultured hyperpigmented spots, in vitro human skin substitutes, and mouse skin were treated with PFT or p53 small interfering RNA, the expression of melanogenic cytokines and their receptors was significantly decreased, as were levels of tyrosinase and melanogenesis. Taken together, these data reveal the essential role of p53 in hyperpigmentation of the skin via the regulation of paracrine-cytokine signaling, both in keratinocytes and in melanocytes.
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PMID:The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. 1909 8

The results of immunophenotyping investigations of periferal blood granulocyte and lymphocyte population, number of p53+ and Bcl-2+ in 57 patients (among them 18 persons suffered after the Chernobyl NPP accident) with chronic phase of chronic myelogenic leukemia were presented in the article. The reduction of CD34+ granulocytes number, normalization of CD95 cells, negative correlation between the number of CD95 and p53, Bcl-2 granulocytes in Imatinib treated patients in comparison with a control group was determined. The results of the investigation confirmed the efficiency of using BCR/ABL tyrosin kinase inhibitor Imatinib in the treatment of chronic phase of CML.
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PMID:[Periferal blood subpopulation and apoptosis indices in the treatment of chronic myelogenous leukemia with Imatinib]. 1914 25

Excessive UVR ranks among the most harmful environmental influences on human skin. However, the direct impact of UVR on human skin appendages remains to be systematically investigated. Organ-cultured human anagen hair follicles in vitro were irradiated, and reduction of hair shaft elongation, premature catagen entry, and reduced hair matrix keratinocyte proliferation were observed upon irradiation with UVB (20/50 mJ cm(-2)). At 20 mJ cm(-2), apoptotic cell death prevailed (casp-3/p53 activation), whereas at 50 mJ cm(-2), necrotic cell death was predominant (lactate dehydrogenase increase). Mitochondrial common deletion and oxidatively damaged genomic DNA (8-OH-dG) was mainly observed at 20 mJ cm(-2). Follicular melanogenesis and ACTH immunoreactivity drastically declined, but alpha-melanocyte-stimulating hormone remained unchanged, whereas transforming growth factor-beta(2) expression shifted from the outer toward the inner root sheath. Both the number of Giemsa+ mast cells and the degree of mast-cell degranulation increased in the connective tissue sheath (CTS), and CD117 immunoreactivity of CTS cells and matrix keratinocytes was upregulated. Thus, UVR differentially modifies hair growth and cycle, promotes cell death, and induces complex regulatory events in human hair follicles in vitro. The leads from this human organ model, which is a living and human tissue interaction system under physiologically relevant in situ conditions, may encourage its use for general investigation of UV-induced effects as well as for testing possible agents for their UV-protective potency.
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PMID:Profiling the response of human hair follicles to ultraviolet radiation. 1915 39

TRF2 is a telomere-binding protein involved in the protection of chromosome ends. Interestingly, TRF2 is overexpressed in a number of human cancers. Mice with increased TRF2 expression (K5TRF2 mice) display a severe skin phenotype including an increase in skin cancer and premature skin degeneration, which includes increased skin hyperpigmentation and skin dryness; these pathologies are concomitant with dramatic telomere shortening and increased chromosomal instability. Here, we show that K5TRF2 mice have a severe epidermal stem cell (ESC) dysfunction, which is reversed by abrogation of p53 in the absence of rescue of telomere length. Importantly, p53 deletion also rescues severe skin hyperpigmentation in these mice through regulation of alpha-melanocyte-stimulating hormone (alpha-MSH). In addition, skin carcinogenesis is accelerated in K5TRF2/p53(-/-)mice owing to attenuated p21 induction, which enables cell proliferation to resume. Altogether, these results reveal the existence of a DNA damage-dependent checkpoint that acts on ESCs with critically short telomeres and restricts skin proliferation, thereby increasing protection against skin cancer; however, the checkpoint also leads to premature skin aging phenotypes. Finally, the results described here are relevant to our understanding of the pathobiology of those human diseases that are characterized by the presence of critically short telomeres (hereafter referred to as 'telopathies'), such as dyskeratosis congenita which causes severe skin phenotypes including skin hyperpigmentation and skin cancer.
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PMID:Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of the TRF2 telomeric protein on mouse epidermal stem cells. 1925 87

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes, and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells, and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A, and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2, and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va, and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including alpha-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins, and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.
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PMID:Physiological factors that regulate skin pigmentation. 1944 48

It is difficult to evaluate the recurrence and progression potential of pituitary adenomas at presentation. The World Health Organization classification of endocrine tumors suggests that invasion of the surrounding structures, size at presentation, an elevated mitotic index, a Ki-67 labeling index higher than 3%, and extensive p53 expression are indicators of aggressive behavior. Nevertheless, Ki-67 and p53 labeling index evaluation is subject to interobserver variability, and their cutoff values are controversial. In the present study, the prognostic value of Ki-67 and p53 protein labeling indices and their correlation with clinical and radiologic parameters were evaluated using digital image analysis in a series of 166 pituitary adenomas in patients having undergone a follow-up of at least 6 years to evaluate the impact on the recurrence and progression potential of pituitary adenomas. The data were analyzed using the receiver operating characteristic curve and classification and regression tree analysis. The results showed that, in the unstratified data set, the commonly used threshold of the Ki-67 index of 3% has a high specificity (89.5%) but a low sensitivity (53.8%). Unsatisfactory performance results were obtained by performing receiver operating characteristic curve analysis on the p53 labeling index. On the contrary, the classification and regression tree analysis-derived tree demonstrated that each pituitary adenoma subtype has specific prognostic factors. Specifically, the Ki-67 labeling index is a useful prognostic factor in nonfunctioning, adrenocorticotropin, and prolactin adenomas, but with different thresholds. In conclusion, our study emphasizes that the term pituitary adenomas includes different types of tumors, each one having specific prognostic factors.
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PMID:A classification tree approach for pituitary adenomas. 2244 19

Bmi1 is a member of the polycomb repressive complex 1 and plays different roles during embryonic development, depending on the developmental context. Bmi1 over expression is observed in many types of cancer, including tumors of astroglial and neural origin. Although genetic depletion of Bmi1 has been described to result in tumor inhibitory effects partly through INK4A/Arf mediated senescence and apoptosis and also through INK4A/Arf independent effects, it has not been proven that Bmi1 can be causally involved in the formation of these tumors. To see whether this is the case, we developed two conditional Bmi1 transgenic models that were crossed with GFAP-Cre mice to activate transgenic expression in neural and glial lineages. We show here that these mice generate intermediate and anterior lobe pituitary tumors that are positive for ACTH and beta-endorphin. Combined transgenic expression of Bmi1 together with conditional loss of Rb resulted in pituitary tumors but was insufficient to induce medulloblastoma therefore indicating that the oncogenic function of Bmi1 depends on regulation of p16(INK4A)/Rb rather than on regulation of p19(ARF)/p53. Human pituitary adenomas show Bmi1 overexpression in over 50% of the cases, which indicates that Bmi1 could be causally involved in formation of these tumors similarly as in our mouse model.
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PMID:GFAP-Cre-mediated transgenic activation of Bmi1 results in pituitary tumors. 2257 28

Pituitary tumors are classified into typical adenomas, atypical adenomas or carcinomas. Carcinoma represents 0.2% of pituitary tumors and is defined by the presence of metastases. It often presents as invasive and secreting macroadenoma, showing features of malignancy ab initio or over time. The high proliferative index (Ki-67) and immunostaining for p53 protein are common indicators of aggressiveness. We report a 58 years old male with invasive sellar incidentaloma. The hormonal study showed gonadal, thyroid, and somatotrophic failure, with increase of corticotropin (ACTH) and cortisol. Transsphenoidal surgery was performed and histology revealed a typical corticotrophinoma. The successive recurrences over 10 years led to five surgical reoperation and radiotherapy. After the third surgery, cellular atypia, Ki-67 of 27% and immunostaining for p53 were revealed. Subsequently, there were lesions suspicious of metastases (lung and lymph nodes), but the biopsy of the lymph nodes was inconclusive. The patient died before chemotherapy. In this case, the progressive loss of differentiation points to the need for early diagnosis, timely and aggressive treatment.
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PMID:[Pituitary atypical adenoma or malignant corticotrophinoma?]. 2285 8

Induction of tumor cell apoptosis has been recognized as a valid anticancer strategy. However, therapeutic selectivity between tumor and normal cells has always been a challenge. Here, we report a novel anti-cancer compound methyl 3-(4-nitrophenyl) propiolate (NPP) preferentially induces apoptosis in tumor cells through P450-catalyzed reactive oxygen species (ROS) production. A compound sensitivity study on multiple cell lines shows that tumor cells with high basal ROS levels, low antioxidant capacities, and p53 mutations are especially sensitive to NPP. Knockdown of p53 sensitized non-transformed cells to NPP-induced cell death. Additionally, by comparing NPP with other ROS inducers, we show that the susceptibility of tumor cells to the ROS-induced cell death is influenced by the mode, amount, duration, and perhaps location of ROS production. Our studies not only discovered a unique anticancer drug candidate but also shed new light on the understanding of ROS generation and function and the potential application of a ROS-promoting strategy in cancer treatment.
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PMID:Selective induction of tumor cell apoptosis by a novel P450-mediated reactive oxygen species (ROS) inducer methyl 3-(4-nitrophenyl) propiolate. 2338 87

P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumor suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and family members have been implicated in the direct regulation of VDR. This overview summarizes some of the implications of the cross-talk between vitamin D- and p53-signaling for carcinogenesis in the skin and other tissues.
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PMID:Tumor suppression in skin and other tissues via cross-talk between vitamin D- and p53-signaling. 2491 21


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