Biomedical subjects

O Humbey

Publications and source records attributed to O Humbey.

5 recordsLinked to original sources

PubMed2006

Polymorphisms in the p53 pathway.

The p53 tumor suppressor gene continues to be distinguished as the most frequently mutated gene in human cancer; this gene can be found mutated in up to 50% of human tumors of diverse histological type. It is generally accepted that the ability of p53 to induce either growth arrest or programmed cell death in response to diverse stimuli underlies the powerful selection against this protein in the development of cancer. It is somewhat surprising, then, to find p53 and several target genes in this pathway containing polymorphisms that impair their function. The nature of these polymorphic variants, and the mechanism whereby they impair the function of the p53 pathway, are reviewed here-in. The impact of these polymorphisms on cancer risk and the efficacy of therapy are only now becoming unraveled. Of particular relevance in these efforts will be the generation of mouse models of polymorphic variants in p53 and its target genes. Equally important will be better-controlled human studies, where-in haplotypes for p53 (that is, combinations of different polymorphisms in the p53 gene) and for p53-target genes are taken into account, instead of analyses of single gene variants, which have largely predominated to date. Studies in both regards should shed light on an emerging area in cancer biology, the significance of inter-individual differences in genotype on cancer risk, prognosis, and the efficacy of cancer therapy.

Animals↗

PubMed2003

Detection of the human papillomavirus and analysis of the TP53 polymorphism of exon 4 at codon 72 in penile squamous cell carcinomas.

Human papillomaviruses (HPV) are thought to be involved in penile squamous cell carcinomas (SCC). A common polymorphism at codon 72 of exon 4 encoding either arginine (Arg) or proline (Pro) has been shown to affect HPV-mediated degradation of p53 in vitro, and may represent a risk factor for HPV-induced carcinogenesis. The presence of HPV DNA as well as the TP53 polymorphism at codon 72 of exon 4 were investigated in a series of 45 penile SCC. HPV detection and typing were carried out by polymerase chain reaction (PCR) with generic primers (MY09-MY11 and FAP59-FAP64), and type-specific DNA probes. TP53 polymorphism was further investigated using Denaturing Gradient Gel Electrophoresis (DGGE). HPV DNA was detected in 67% of penile SCC and 32% of benign lesions (BL) (P<0.05). Among the TP53 amplified samples, the rate of Arg homozygosity in penile SCC was 61% compared with 68% in BL (non-significant (NS)). Our results demonstrate a strong association between penile SCC and the presence of HPV DNA. The TP53 Arg/Arg genotype does not appear to represent a risk factor for the development of genital SCC in men, and no correlation was found between the TP53 polymorphism at codon 72 and the presence of HPV DNA.

Adult↗

PubMed2003

[Non-melanoma skin cancers and human papillomavirus].

Ultraviolet radiation (UV) is considered as a key environmental risk factor of non-melanoma skin cancer (NMSC), but other factors such as immunological status, genetic predisposition and infection by human papillomavirus (HPV) may also be involved. Although there is overwhelming epidemiological and molecular evidence that indicates a direct role for specific mucosal HPV-types in anogenital cancers, in particular cervical cancer, the pathogenic role of HPV in the development of NMSC remains speculative. The association between HPV and NMSC was first identified in patients with epidermodysplasia verruciformis (EV) and later in recipients of organ transplants. All these patients develop NMSC at sun-exposed sites. Cutaneous and mucosal HPV-DNA have been detected in about 60 to 90 p. 100 of NMSC, but also in benign epithelial lesions, and even in normal skin. However and although at a lower rate (about 40 p. 100), HPV-DNA have also been detected in normal skin, in particular in hair follicles, and in premalignant lesions and in NMSC from non-EV and immunocompetent subjects. Furthermore, no particular HPV type predominates and the viral load in NMSC seems lower than in benign epithelial lesions. Although all these findings argue against a direct involvement of HPV in NMSC, they may suggest a "hit and run" mechanism which no longer requires the viral agent but the activity of HPV oncoproteins. High risk mucosal HPV-types encode two major oncoproteins, E6 and E7, which inactivate two suppressor proteins, p53 and pRb respectively, and are sufficient for host-cell immortalization. A polymorphism resulting in either a proline or an arginine at codon 72 may also be a relevant risk factor for mucosal HPV-types-associated NMSC. By contrast, E6 of skin HPV-types fails to interact with p53, but prevents infected cells from UV-induced apoptosis leading thus to the propagation of deleterious UV-induced mutations. Immunosuppressive activities of HPV E6 and E7 proteins permit persistent HPV infection and the impairment of immunologic removal of UV-damaged cells. These results support a role for HPV infection in skin carcinogenesis as a co-factor in association with UV and immunosuppression.

Apoptosis↗

PubMed2001

[Melanoma: role of ultraviolet radiation: from physiology to pathology].

EPIDEMIOLOGIC DATA: The frequency of malignant melanoma, by far the most fatal skin cancer, has increased by a factor of approximately 15 in the past 60 years. The factors underlying this rapid increase are incompletely understood, although ultraviolet radiations are likely strongly implicated. Epidemiologic studies demonstrate the role of altered patterns of sun exposure, and overexposition to UVA radiation, as confirmed by experimental data on animal models. BIOLOGICAL ASPECTS: Melanin produced by melanocytes has a photoprotective function in the skin, whereas UVB-induced DNA damage enhance the repair capacity of these cells. However, this photoprotective effect is not induced by intense intermittent sun exposure. In addition, melanocytes demonstrate resistance to UVB-induced apoptosis and are thus at high risk for incorporating UV-induced mutations. MOLECULAR ASPECTS: Different mutations in susceptibility genes (CDKN2A, INK4), or in genes implicated in control of cell cycle or maintenance of cell integrity (DNA repair) are involved in initiation and promotion steps of melanocarcinogenesis. Moreover, tumor progression is stimulated by UVB through the activation of different target genes that are implicated in control of melanoma environment (immune surveillance, angiogenesis, growth factors...).

Adolescent↗

PubMed2000

[Human papillomaviruses, cell cycle and cervical cancer].

Human papillomaviruses (HPVs) are associated with a broad spectrum of cutaneous and mucosal lesions. Until now, more than 120 genotypes have been identified. Most HPVs are associated with benign lesions. Nevertheless certain HPV types are frequently found in carcinomas. For instance, HPV 16 and 18 which are frequently associated with cervical cancer, are capable of immortalizing and transforming primary keratinocytes. The mechanism of transformation is linked to the viral genome integration into the cell's DNA, accompanied by an overexpression of the E6 and E7 genes. The viral gene products interact with cellular proteins that regulate the cycle progression. In particular, the E6 protein binds to the p53 and the E7 protein binds to the p105(Rb). The inactivation of both cellular proteins distorts the cell cycle and results in genetic instability and cellular gene alterations. This article reviews the role of the viruses in the carcinogenesis, the genome structure and the gene expression of HPVs. It also addresses the cell cycle regulation with a focus on the role of HPVs in cell transformation.

Cell Cycle↗