1 At the molecular level, 53% of germ line P53 mutations are G:C to A:T transitions at CpG, which are naturally occurring sites of methylation in the genome.28 Recently mutations of the oligomerization domain have been isolated from an LFS and an LFL
family affecting respectively codon 344 (Leu to Pro) and 337 (Arg to Cys). Point mutations in the oligomerization domain can disrupt P53 function.26 Although the mutations spread over essentially the entire gene, nevertheless there is considerable clustering of mutations within the central region of the protein. The majority of mutations are missense, Inhibitors,research,lifescience,medical with alterations at only five codons representing 25% of all known mutations (codons 175, 245, 248, 249 and 273).14 Mutations in codons 248, 273, 245, 175, and 282 are the most common in both sporadic tumors and the germline, Inhibitors,research,lifescience,medical although their ranking is somewhat different sporadic tumors and the germ line.27 In addition, Mutant P53 gene may have a role in the persistence of cancer cells and development of basal and squamous cell carcinomas.29 Mutations of CHK1 and CHK2 in LFS selleck chemicals llc checkpoint kinase 2 (Chk2) is a DNA damage-activated protein kinase that lies downstream of ATM in this pathway. Heterozygous germ line mutations in Chk2 have been identified in a subset of Inhibitors,research,lifescience,medical patients with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype, suggesting
that Chk2 is a tumor suppressor gene.27 These two are essential for prevention of neoplastic transformation. Several proteins involved in this pathway including P53, breast cancer type 2 suceptibility (BRCA1), and Ataxia telangiectasia mutated (ATM) are frequently mutated in human cancer. Inhibitors,research,lifescience,medical In a kindred with Li-Fraumeni syndrome
(LFS) selleck screening library without an inherited TP53 mutation, previously has been reported a truncating mutation (1100delC) in Checkpoint kinase 2 (CHK2), encoding a kinase that phosphorylates P53 on Ser20. And also CHK2 missense mutation (R145W) has been reported in another LFS family. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding Inhibitors,research,lifescience,medical tumor specimens, and neither tumor harbors a somatic TP53 mutation.30 The cell cycle checkpoint kinases CHK1 and CHK2 act upstream of P53 in DNA damage responses. CHK2 is a human homologue of Cds1 in Schizosaccharomyces pombe and Rad53 in Saccharomyces cerevisiae, and CHK1 is a human homologue of the S. pombe checkpoint kinase Chk1.31 Brefeldin_A MDM2: A Master Regulator of P53 Stability and Activity MDM2 was originally identified as an amplified gene on double minute chromosomes in spontaneously transformed 3T3 cells. MDM2 negatively regulates P53 stability and transcriptional function. Its human counterpart, the human homologue of murine (HDM2) encodes a 90-kDa (491 amino acids) nuclear phosphoprotein that is over expressed in several types of human tumors. The HDM2 gene spans f33 kb of genomic DNA and also consists of 12 exons.