/pdf/inhibitors-of-mammalian-g1-cyclin-dependent-kinases-38eef2u6ay.pdf

Inhibitors of mammalian G1 cyclin-dependent kinases.

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

Role of the INK4a locus in tumor suppression and cell mortality

Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF

Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame

Background A gene on chromosome 9p, p16INK4, has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the function of the p16 INK4 protein (p16M alleles) cosegregated with the disease. By contrast, in the other nine kindreds the mutation did not alter the function of p16 INK4 (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of families. Methods We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in the kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of cancer cases observed with the number expected. Results The risk of invasive melanoma was increased by a factor of 75 in kindreds with p16M alleles and a factor of 38 in kindreds with p16W ...

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

Cell division is controlled by a series of positive and negative regulators which act at sequential points throughout the cell cycle. Disturbance of these checks could contribute to cancer by allowing excessive cell proliferation. The point in G1 at which cells irrevocably commit to DNA synthesis is controlled by protein complexes consisting of cyclin-dependent kinases (CDK4 or CDK6) and cyclins (D1, D2 or D3). These complexes are inhibited by low molecular weight proteins, such as pl6(INK4) (refs 1,2), p15(INK4B) (ref. 3) and pl 8 (ref. 4). Deletion or mutation of these CDK- inhibitors could lead to unchecked cell growth, suggesting that members of the p16(INK4) family may be tumour suppressor genes. The recent detection of p16(INK4) (MTS1) mutations in familial melanoma kindreds, many human tumour cell lines, and primary tumours is consistent with this idea. Previously, we described eight germline p16(INK4) substitutions in 18 familial melanoma kindreds. Genetic analyses suggested that five mutations predisposed carriers to melanoma, whereas two missense mutations had no phenotypic effect. We now describe biochemical analyses of the missense germline mutations and a single somatic mutation detected in these families. Only the melanoma-predisposing mutants were impaired in their ability to inhibit the catalytic activity of the cyclin D1/CDK4 and cyclin D1/CDK6 complexes in vitro. Our data provide a biochemical rationale for the hypothesis that carriers of certain p16(INK4) mutations are at increased risk of developing melanoma.

Mutations associated with familial melanoma impair p16INK4 function

ObjectivePeroxisome proliferator-activated receptor γ (PPARγ) agonists can cause peripheral edema in susceptible individuals. To investigate the mechanistic basis underlying this adverse event, we performed a candidate gene analysis of patients enrolled in clinical trials of muraglitazar, an investi

Genetic and gene expression studies implicate renin and endothelin-1 in edema caused by peroxisome proliferator-activated receptor gamma agonists.

The present invention provides polynucleotides and polypeptides corresponding to novel gene sequences associated with cardiovascular disorders. The present invention also provides polynucleotide fragments corresponding to the genomic and/or coding regions of these genes that comprise at least one polymorphic site per fragment. Allele-specific primers and probes that hybridize to these regions, and/or which comprise at least one polymorphic site are also provided. The polynucleotides, primers, and probes of the present invention are useful in phenotype correlations, paternity testing, medicine, and genetic analysis. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing the polypeptides of the present invention. The present invention further relates to diagnostic and therapeutic methods for applying these novel polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders, particularly cardiovascular diseases related to these polypeptides. The present invention further relates to screening methods for identifying agonists and antagonists of the polynucleotides and polypeptides of the present invention.

Koustubh Ranade

Papers

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

Mutations associated with familial melanoma impair p16INK4 function

Genetic and gene expression studies implicate renin and endothelin-1 in edema caused by peroxisome proliferator-activated receptor gamma agonists.

Human sterol response element binding protein 1 (SREBP1) single nucleotide polymorphisms

Procédés d'identification de sujets présentant un risque accru de réponse à des inhibiteurs de dpp-iv