Detection of tumor cells in blood using CD45 magnetic cell separation followed by nested mutant allele‐specific amplification of p53 and K‐ras genes in patients with colorectal cancer

Iinuma, Hisae; Okinaga, Kota; Adachi, Miki; Suda, Kazufumi; Sekine, Toshiyuki; Sakagawa, Koichi; Baba, Yasuo; Tamura, Junko; Kumagai, Harumi; Ida, Akimitsu

doi:10.1002/1097-0215(20000720)89:4<337::aid-ijc4>3.3.co;2-i

Cited by 24 publications

(35 citation statements)

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“…Moreover, this specific mutation was reported in canine thyroid carcinoma (41). Arginine at codon 209 is mutated in 69 tumors, among which five of these tumors harbor the exact arginine-to-lysine alteration including B cell chronic lymphocytic leukemia (42), esophageal carcinoma (43), skin cancer (44), uterine cervical cancer (45), and colon cancer (46).…”

Section: Discussion P53 Mutations In Human Cancer and In Underground-mentioning

confidence: 99%

Evolution of p53 in hypoxia-stressedSpalaxmimics human tumor mutation

Ashur‐Fabian

Avivi

Trakhtenbrot

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

108

134

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The tumor suppressor gene p53 controls cellular response to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and͞or apoptosis. Inactivation of p53, found in 40 -50% of human cancers, confers selective advantage under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its entire life cycle underground at decidedly lower oxygen tensions than any other mammal studied. Because a wide range of respiratory adaptations to hypoxic stress evolved in Spalax, we speculated that it might also have developed hypoxia adaptation mechanisms analogous to the genetic͞epige-netic alterations acquired during tumor progression. Comparing Spalax with human and mouse p53 revealed an arginine (R) to lysine (K) substitution in Spalax (Arg-174 in human) in the DNAbinding domain, identical to known tumor associated mutations. Multiple p53 sequence alignments with 41 additional species confirmed that Arg-174 is highly conserved. Reporter assays uncovered that Spalax p53 protein is unable to induce apoptosisregulating target genes, resulting in no expression of apaf1 and partial expression of puma, pten, and noxa. However, cell cycle arrest and p53 stabilization͞homeostasis genes were overactivated by Spalax p53. Lys-174 was found critical for apaf1 expression inactivation. A DNA-free p53 structure model predicts that Arg-174 is important for dimerization, whereas Spalax Lys-174 prevents such interactions. Similar neighboring mutations found in human tumors favor growth arrest rather than apoptosis. We hypothesize that, in an analogy with human tumor progression, Spalax underwent remarkable adaptive p53 evolution during 40 million years of underground hypoxic life.

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Section: Discussion P53 Mutations In Human Cancer and In Underground-mentioning

confidence: 99%

Evolution of p53 in hypoxia-stressedSpalaxmimics human tumor mutation

Ashur‐Fabian

Avivi

Trakhtenbrot

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

108

134

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“…Arginine at codon 209 was found mutated in 69 tumors, including five tumors that harbor the exact arginine-to-lysine replacement. [35][36][37][38][39] Multiple alignment performed among 44 species indicated that the amino acid at position 209 in humans is not a Spalax-unique change. Actually, there is a vast variability at this nonconserved region, with 10 different amino acid possibilities among the species examined.…”

Section: Spalax P53 Biologymentioning

confidence: 99%

p53: A Key Player in Tumoral and Evolutionary Adaptation: A Lesson from the Israeli Blind Subterranean Mole Rat

Avivi¹,

Ashur‐Fabian²,

Amariglio³

et al. 2005

Cell Cycle

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ABSTRACTp53 is a transcription factor involved in maintaining genomic integrity by regulating genes involved in cell cycle arrest, DNA repair, and programmed cell death. Various post transcriptional modifications result in activated p53 with varying binding affinity to its targets. The other members of the p53 family (p63, p73) and associated proteins also contribute to the specificity of gene activation resulting in the final cell responses. p53 is commonly mutated in human cancer and is activated by diverse cellular events, including hypoxia. Many sources of genetic diversity, including random or stress-related mutagenesis, affect normal species evolution. The blind subterranean mole rat lives in sealed underground tunnels, subjected to routine hypoxia due to abrupt and sharp changes in O2 supply. We cloned the mole rat's p53 gene and identified two amino acid substitutions in its binding domain, in the same positions that are mutated in cancer. These substitutions lead to increased p53 activation of DNA-repair elements and reduced activation of apoptotic genes. We propose that sequence-specific changes in the mole rat's p53 gene provide an example of how transcription factors that regulate many genes can also account for rapid and broad phenotypic diversity by altering the binding affinity to individual target genes.

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“…16 In contrast to this, tumor cells in the course of dedifferentiation may lose surface antigens (e.g., HEA) and the CK pattern. This may result in fewer target binding sites for the magnetic beads used in a positive selection procedure, consequently leading to false-negative results.…”

Section: Discussionmentioning

confidence: 99%