Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor protein p53 is a phosphoprotein that is activated by DNA damage. It is involved in the decision whether the cells should stop replication and proceed to repair their DNA, or to die by apoptosis. In the present study, we evaluate the effect of some treatment modalities on the expression of p53 in facial skin. Biopsy specimens were obtained from the facial skin of 20 patients before and after treatment using topical tretinoin (11 cases), TCA chemical peeling (5 cases) and dermabrasion (4 cases). Biopsy specimens were also obtained from 12 control subjects representing the same age groups of the patients. Topical tretinoin therapy was found to induce a significant decrease in the expression of p53 up to 6 months of therapy followed by a significant increase after 10 months of therapy. On the contrary, superficial TCA peeling did not induce any statistically significant change in the expression of p53. On the other hand dermabrasion was found to induce a significant decrease in the level of expression of p53 in biopsies obtained after complete re-epithelialization followed by a significant increase. These changes in the expression of p53 may play a role in mediating the effects of such treatment modalities on the epidermis, as well as prevention of actinic neoplasia by adjusting any disturbance in the proliferation/apoptosis balance observed in photoaged facial skin.
Eur J Dermatol
PMID:Effect of topical tretinoin, chemical peeling and dermabrasion on p53 expression in facial skin. 1469 85

We report a case of Bowen's disease on the sole presenting clinically as an exophytic, blackish-grey, verrucous tumour, and showing human papillomavirus (HPV) type 16 on analysis with polymerase chain reaction. Positive stains for HPV particles by immunohistochemical analysis were limited to several cell nuclei at the upper stratum Malpighii. However, all the tumour cells in the epidermis exhibited strong and diffuse nuclear and cytoplasmic stains for the tumour suppressor protein p16INK4a. We speculate that dysregulation of the retinoblastoma/p16INK4a pathway may be involved in the pathogenesis of the lesion, and p16INK4a overexpression might serve as a useful surrogate marker for identifying Bowen's disease harbouring high-risk types of HPV infection.
Br J Dermatol 2005 Jan
PMID:Bowen's disease on the sole: p16INK4a overexpression associated with human papillomavirus type 16. 1565 21

The molecular factors and events that characterize susceptibility and outcome in cutaneous basal cell carcinoma (BCC) have been the focus of much research interest. As a result, we are beginning to understand the complex relationships between exposure to ultraviolet radiation (UVR), host response and the resulting damage to key genes that characterize these tumours. In this review, we will focus on genetic factors that influence susceptibility and outcome. While the search for susceptibility genes has generally resulted in the identification of low penetrance allelic variants, studies on modifier genes influencing outcome variables such as tumour number, age of onset and tumour subtype have identified factors with higher potential impact. Here we will briefly describe some recent work on the genetic basis of the immune response to UVR, the effect of UVR on the generation of reactive oxygen species and their detoxification, and the role of onco- and tumour suppressor genes. Areas for further research are highlighted, together with a consideration of possible applications in clinical practice.
Clin Exp Dermatol 2005 Jan
PMID:Basal cell carcinoma: from host response and polymorphic variants to tumour suppressor genes. 1566 4

Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition that results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papillary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous mutations in the gene encoding fumarate hydratase have been found to underlie both conditions. Fumarate hydratase is an enzyme that catalyses the conversion of fumarate to malate in the Kreb's cycle and may also function as a tumour suppressor gene. We report a family with multiple leiomyomas, uterine fibroids and papillary renal cell cancer. The proband is a 77-year-old Polish woman who developed multiple cutaneous leiomyomas on her right upper arm in her thirties and subsequently underwent a hysterectomy for uterine fibroids in her forties. She has four offspring: her eldest daughter also has skin and uterine leiomyomas with a similar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two youngest daughters are unaffected. DNA sequencing in all the affected individuals disclosed a heterozygous G-->C substitution at nucleotide 173 of the fumarate hydratase gene, that converts an arginine residue (CGA) to proline (CCA). This missense mutation has not been reported previously and is designated R58P. Interestingly, the clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop skin leiomyomas in the future but the risk of renal cancer is difficult to predict. Nevertheless, detection of this mutation has important implications for screening and genetic counselling in this and other family members.
Clin Exp Dermatol 2005 Jan
PMID:Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. 1566 10

Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.
Clin Exp Dermatol 2006 Jan
PMID:Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene. 1630

It has been suggested that the up-regulation of the tumour suppressor p16 gene and induction of senescence protect the phenotype of psoriatic involved skin from malignant transformation. On the other hand, Id1, which is inversely correlated with p16 has been shown to be up-regulated in psoriatic involved skin. To test the hypothesis that there may be an altered regulation of p16 in psoriatic involved skin, we have measured genes involved in the Igf-1 receptor signalling through the Ras/MAPK cascade. Igf-1R, IGFBP3, hRas, Ets2, JunB, Egr-1, Id1, MIDA1 and p16 gene expressions were measured using quantitative real-time PCR in total RNA isolated from punch biopsies from psoriatic involved (n = 9) and uninvolved skin (n = 9) and from cutaneous squamous cell cancer (SCC) involved (n = 8) and uninvolved skin (n = 8). The IGFBP3, hRas, JunB, Egr-1, Id1 and MIDA1 genes were up-regulated in psoriatic involved skin compared with uninvolved skin. The p16, JunB and MIDA1 genes were up-regulated in SCC involved skin compared with uninvolved skin. Our results indicate that there may be a balance between the proliferation and induction of senescence in psoriasis. This balance may vary and the psoriatic involved skin represented in this study appears to be in a proliferative state rather than senescence. Furthermore, we suggest that the noted up-regulation of JunB, which has been shown to up-regulate p16, in combination with the previously reported elevation of p16 expression in psoriatic involved skin, may indicate activation of a pathway by which JunB may protect the psoriatic plaque by inducing p16 in an event of malignant stress.
Arch Dermatol Res 2006 Apr
PMID:Expression of genes involved in the regulation of p16 in psoriatic involved skin. 1655 41

The transcription factor p53 is mutated in most keratinocyte carcinomas (nonmelanoma skin cancers). In these tumours, the gene bears the trace of its mutagen, sunlight. Sunlight-induced p53 mutations are also seen in skin precancers and even sun-exposed skin, which harbours thousands of p53-mutant keratinocyte clones. Normal p53 is upregulated by sunlight exposure, after which it acts as a tumour suppressor in several ways: increasing DNA repair, arresting the cell cycle and inducing apoptosis of badly damaged keratinocytes. This UV-induced upregulation has been used as an assay for assessing the effectiveness of sunscreens. Once mutated, however, p53 renders cells apoptosis-resistant and therefore less sensitive to sunlight overexposure than normal cells. This reversal of roles drives clonal expansion of precancerous keratinocytes.
Br J Dermatol 2006 May
PMID:Roles of the transcription factor p53 in keratinocyte carcinomas. 1671 10

The last decade has seen a considerable improvement in the understanding of the biology of melanoma. Advances have come in the understanding of the importance of critical oncogenes and tumour suppressor genes, epigenetic phenomena, signalling pathways, drug resistance mechanisms, the pivotal role of the local immune system, and the importance of cell-cell and cell-matrix interactions. Many of these pathways and interactions include potentially 'drugable' targets. These developments have allowed the identification and/or design of a range of new, targeted therapies. Evaluation of these new drugs has brought a whole new series of challenges. These include identification of appropriate pre-clinical models, overcoming the redundancy in-built in complex biological systems, identification of appropriate molecular and clinical endpoints to show that the drug is hitting the target, how to combine treatments, and new toxicities. For the first time, there is the possibility of personalized treatment for melanoma patients, based on individual host and tumour characteristics. This paper discusses the range of new drugs and targets have been identified, the outcome of clinical trials, and the directions for future advances.
Exp Dermatol 2008 May
PMID:Systemic therapy for metastatic malignant melanoma--from deeply disappointing to bright future? 1831 90

Basal cell carcinoma is the most common human malignancy in populations of European origin, and Australia has the highest incidence of basal cell carcinoma in the world. Great advances in the understanding of the genetics of this cancer have occurred in recent years. Mutations of the patched 1 gene (PTCH1) lead to basal cell carcinoma predisposition in Gorlin syndrome. PTCH1 is part of the hedgehog signalling pathway, and derangements within this pathway are now known to be important in the carcinogenesis of many different cancers including sporadic basal cell carcinoma. The molecular biology of the hedgehog pathway is discussed, and mouse models of basal cell carcinoma based on this pathway are explored. New developments in non-surgical treatment of basal cell carcinoma are based on this knowledge. Other genes of importance to basal cell carcinoma development include the tumour suppressor gene P53 and the melanocortin-1 receptor gene. In addition, we discuss molecules of possible importance such as the glutathione-S-transferases, DNA repair genes, cyclin-dependent kinase inhibitor 2A, Brahma and connexins. Evidence of familial aggregation of this cancer is explored and supports the possibility of genetic predisposition to this common malignancy.
Australas J Dermatol 2010 May
PMID:Genetics of basal cell carcinoma. 2054 11

Multiple cutaneous and uterine leiomyomatosis (MCUL)/hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM 150800/OMIM 605839) is a rare hereditary disorder leading to the development of benign cutaneous and uterine smooth muscle tumours in young adults.(1,2) This disease is characterized by an increased risk of developing renal cell carcinomas.(3) It results from dominantly inherited autosomal mutations in the fumarate hydratase (FH) gene.(4) This gene encodes a Krebs cycle enzyme, present in both cytosolic and mitochondrial compartments, and probably acts as a tumour suppressor gene. We report a 22-year-old man affected by cutaneous leiomyomatosis associated with cutis verticis gyrata, disseminated collagenoma and Charcot-Marie-Tooth disease, who was harbouring the novel FH gene mutation c.821C > T, p.Ala274Val.
Br J Dermatol 2010 Dec
PMID:Novel FH mutation in a patient with cutaneous leiomyomatosis associated with cutis verticis gyrata, eruptive collagenoma and Charcot-Marie-Tooth disease. 2056 Sep 59


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