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R W Wiseman

Publications and source records attributed to R W Wiseman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11.

The BRCA1 gene is in large part responsible for hereditary human breast and ovarian cancer. Here we report the isolation of the murine Brca1 homologue cDNA clones. In addition, we identified genomic P1 clones that contain most, if not all, of the mouse Brca1 locus. DNA sequence analysis revealed that the mouse and human coding regions are 75% identical at the nucleotide level while the predicted amino acid identity is only 58%. A DNA sequence variant in the Brca1 locus was identified and used to map this gene on a (Mus m. musculus Czech II x C57BL/KsJ)F1 x C57BL/KsJ intersubspecific backcross to distal mouse chromosome 11. The mapping of this gene to a region highly syntenic with human chromosome 17, coupled with Southern and Northern analyses, confirms that we isolated the murine Brca1 homologue rather than a related RING finger gene. The isolation of the mouse Brca1 homologue will facilitate the creation of mouse models for germline BRCA1 defects.

Amino Acid Sequence↗
PubMed1995

Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers.

We have utilized a genetic selection system in yeast to identify novel estrogen-responsive genes within the human genome and to define the sequences in the BRCA-1 gene responsible for its estrogen responsiveness. This approach led to the identification of a new subclass within the Alu family of DNA repeats which have diverged from known Alu sequences and have acquired the ability to function as estrogen receptor-dependent enhancers. Importantly, these new elements confer receptor-dependent estrogen responsiveness to a heterologous promoter when assayed in mammalian cells. This transcriptional activity can be attenuated by the addition of either of three different classes of estrogen receptor antagonists, indicating that these elements function as classical estrogen receptor-dependent enhancers. Furthermore, this enhancer activity is restricted to a specific subset of DNA repeats because consensus Alu elements of four major subfamilies do not respond to the estrogen receptor. Previously, most Alu sequences have been considered to be functionally inert. However, this work provides strong evidence that a significant subset can confer estrogen responsiveness upon a promoter within which they are located. Clearly, Alu sequences must now be considered as important contributors to the regulation of gene transcription in estrogen receptor-containing cells.

Animals↗
PubMed1995

Creatine kinase equilibration follows solution thermodynamics in skeletal muscle. 31P NMR studies using creatine analogs.

The hypothesis tested was whether creatine kinase (CK) equilibrates with its substrates and products in the cytosol as if in solution. We used the creatine analogs cyclocreatine (cCr) or beta-guanidopropionate (beta GPA) to test if mass action ratios (gamma) for CK in muscle could be predicted from combined equilibrium constants (Kcomb) measured in solutions mimicking the intracellular environment. Mice were fed cCr or beta GPA and their muscles assayed for substrates and products of the CK reaction by 31P NMR spectroscopy and high performance liquid chromatography. After three weeks of feeding, gamma was indistinguishable from Kcomb in cCr-treated muscles demonstrating both PCr/Cr and phospho-analog/analog must have equilibrated with a constant and uniform cellular ATP/ADP ratio. In beta GPA-treated muscles, gamma was smaller than Kcomb due to a higher content of muscle beta GPA. Feeding beta GPA for 9-12 weeks resulted in a closer agreement between Kcomb and gamma, suggesting ATP/ADP ratios are not uniform within the muscle perhaps due to transient metabolic stress in some cells. From this analysis it follows that calculation of free ADP from the CK equilibrium for a heterogeneous population of cells with respect to total Cr and ATP content is correct only if chemical potentials of these cells are uniform.

Adenosine Diphosphate↗
PubMed1994

Allelotype analysis of mouse lung carcinomas reveals frequent allelic losses on chromosome 4 and an association between allelic imbalances on chromosome 6 and K-ras activation.

We generated allelotypes of 38 methylene chloride-induced lung carcinomas from female C57BL/6J x C3H/6J F1 (hereafter called B6C3F1) mice. Two or more polymorphic markers per autosome, most of them microsatellites, were examined for loss of heterozygosity. Allelic losses throughout the genome were generally infrequent except for markers on chromosome 4, which were lost in approximately one-half of the carcinomas. Analysis of lung adenomas indicated that chromosome 4 loss was associated with malignant conversion. In addition, chromosome 4 loss were specific for lung carcinomas based on comparison to methylene chloride-induced liver tumors and additional studies of lung tumors from a variety of treatment protocols and different mouse strains. Preferential loss of the maternal chromosome 4 was observed in B6C3F1 carcinomas. Analyses of additional tumors induced in mice from two reciprocal crosses, A/J x C3H/HeJ F1 (hereafter called AC3F1) and C3H/HeJ x A/J F1 (hereafter called C3AF1), provided evidence for the inactivation of one allele of the putative chromosome 4 tumor suppressor gene by parental imprinting. Most B6C3F1 tumors lost all chromosome 4 markers examined, suggesting nondisjunction events. In contrast, several C3AF1 and AC3F1 tumors appeared to have interstitial deletions that defined the smallest region of overlap as a 9-cM interval between Ifa-2 and D4Nds2. The homologous region on human chromosome 9p21-22 is frequently lost in a variety of tumors including lung cancers. A candidate tumor suppressor gene, MTS1, is located in this region, which is homozygously deleted or mutated in cell lines derived from a variety of human tumors. Finally, an association between K-ras gene activation and allelic imbalances on chromosome 6 was observed for B6C3F1 lung tumors.

Alleles↗
PubMed1994

Deletion mapping of a putative tumor suppressor gene on chromosome 4 in mouse lung tumors.

Genetic and molecular studies have implicated the region of the alpha-interferon gene cluster on mouse chromosome 4 as the location of a putative tumor suppressor gene. A region of homology on human chromosome 9p21-22 that is frequently deleted in multiple human cancers has recently been found to contain a candidate tumor suppressor gene called multiple tumor suppressor-1 (MTS1); which was previously shown to encode an inhibitor of cyclin-dependent kinase 4. We performed loss of heterozygosity and deletion analyses to map the most commonly deleted region on chromosome 4 in F1 hybrid mouse lung tumors. Ten simple sequence length polymorphism markers were analyzed with focus on the alpha-interferon region. Allelic losses were detected in 29 of 61 (48%) of the lung adenocarcinomas but in only 1 of 38 (3%) of the lung adenomas examined. In most cases, the losses appeared to occur by nondisjunction. However, in three carcinomas, we detected homozygous deletions that overlapped at simple sequence length polymorphism marker D4MIT77. These data suggest a critical region of about 2 cM immediately distal to the alpha-interferon locus as the likely domain of a novel tumor suppressor gene on mouse chromosome 4, the loss of which appears to be involved in the progression of mouse lung tumorigenesis.

Adenocarcinoma↗
PubMed1994

Allelotyping of butadiene-induced lung and mammary adenocarcinomas of B6C3F1 mice: frequent losses of heterozygosity in regions homologous to human tumor-suppressor genes.

To identify the potential involvement of tumor-suppressor gene inactivation during neoplastic development in B6C3F1 mice, genetic losses were determined from allelotypes of butadiene-induced lung and mammary adenocarcinomas. By using length polymorphisms in restriction fragments and simple sequence repeats, or "microsatellites," markers on each autosome were analyzed for allele losses in tumor DNAs. Losses of heterozygosity on chromosome 11 were observed at several loci surrounding the p53 tumor-suppressor gene (Trp53) in 12 of 17 mammary tumors and 2 of 8 lung tumors. Although most of these alterations appeared to result from nondisjunction, at least two examples of somatic recombination or deletion were also observed. Southern analysis revealed a homozygous deletion of the remaining Trp53 allele of one of these mammary tumors. Losses of heterozygosity were also detected at the Rb-1 tumor-suppressor gene in 7 of 17 mammary tumors and 1 lung tumor. Finally, frequent allele losses were observed on chromosome 4 in lung tumors. Analysis of nine chromosome 4 loci defined an interstitial deletion containing the Ifa gene cluster in one of the lung tumors. A tumor-suppressor gene was previously mapped to this region of chromosome 4 in studies with somatic cell hybrids. In addition, homozygous deletions have been reported in a homologous region of human chromosome 9p for acute lymphocytic leukemias, glioblastomas, melanomas, and lung carcinomas. These findings suggest that the inactivation of tumor-suppressor genes including Trp53, Rb-1, and an unidentified gene on chromosome 4 plays a significant role during carcinogenesis in mice.

Adenocarcinoma↗
PubMed1994

Mutation analysis of the THRA1 gene in breast cancer: deletion/fusion of the gene to a novel sequence on 17q in the BT474 cell line.

We have previously described a common region of deletion and allele loss on chromosome 17q in sporadic breast cancers that is likely to contain a tumor suppressor gene. The region, mapped to 17q12-q21, was bordered by D17S250 and D17S579 on the centromeric and telomeric sides, respectively. This deletion region overlaps the BRCA1 locus, which predisposes to familial breast and ovarian cancer. The most frequent loss of heterozygosity was observed at the thyroid hormone receptor alpha (THRA1) locus. Southern analysis revealed a rearrangement of THRA1 in the BT474 breast cancer cell line. This rearrangement represented a deletion of exons 8-10 of one THRA1 allele that was also coamplified with ERBB2. Northern blots showed two mutant transcripts in BT474 cells. Analysis of the mutant transcripts revealed fusion of the THRA1 exon 7 by splicing to a novel sequence designated BTR for "BT474 transcribed rearrangement." BTR was found to be highly conserved and mapped to 17q. The deletion in BT474 cells spans the entire BRCA1 region. To search for additional mutations in the THRA1 gene, all nine protein-encoding exons of THRA1 were examined for point mutations via single strand conformation analysis in a series of primary breast tumors, breast cancer cell lines, and lymphoblastoid cell lines derived from the youngest affected members of several German breast cancer families. No point mutations were detected, including the unrearranged THRA1 allele in BT474. We have thus excluded THRA1 as a commonly mutated sporadic breast cancer tumor suppressor gene and as the BRCA1 gene.

Amino Acid Sequence↗
PubMed1994

Infrequent p53 mutations in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in BALB/c and p53 hemizygous mice.

We conducted experiments to determine if p53 alterations, which are frequent in human breast cancers, were also common in murine mammary tumors. In 13 mammary tumors from 7,12-dimethylbenz[a]anthracene (DMBA)-treated BALB/c mice were immunohistochemically analyzed for overexpression of p53; p53 protein was not detectable. Three of the tumors were established as cell lines in vitro. p53 protein was rarely detected at passage 4 in these lines but was overexpressed by passage 8 in two of them. The p53 nucleotide sequence was shown to be wild type in one primary mammary tumor and in the two p53-overexpressing cell lines. One cell line that overexpressed p53 in vitro was implanted into BALB/c mice. The resulting tumors retained the wild-type p53 nucleotide sequence but no longer expressed detectable levels of p53 protein, suggesting that the overexpression of wild-type p53 was related to in vitro culture conditions. The effect of DMBA on mammary-tumor development was also tested in mice rendered hemizygous for p53. These mice and wild-type littermate controls had no differences in susceptibility to induction of mammary tumors by oral administration of DMBA. Furthermore, Southern blot hybridization detected no gross alterations in the wild-type p53 allele in mammary tumors from the p53-deficient mice. Point mutation of the wild-type p53 allele was also infrequent in the DMBA-induced mammary tumors from hemizygous p53 mice; it occurred in only one of seven tumors. Thus, the p53 gene is apparently not a primary target for genetic alterations in DMBA-induced mammary tumors. Next, we examined mammary tumors derived from D1 and D2 transplantable hyperplastic alveolar nodule (HAN) outgrowths, which rapidly form tumors containing Ha-ras mutations after DMBA treatment. As ras and p53 mutants can cooperate in transformation, we examined whether D1 and D2 HAN outgrowths have p53 mutations. Unlike in the DMBA-induced primary mammary tumors, nuclear p53 accumulation was observed frequently (10 of 14) in tumors that arose from D1 and D2 HAN outgrowths. Direct sequencing of the entire coding region of the p53 cDNA from six D1 and D2 tumors confirmed that the sequence was wild type. Although wild-type p53 was retained in both DMBA-induced mammary tumors and mammary tumors derived from D1 and D2 preneoplastic outgrowths, wild-type p53 overexpression was detected only in D1 and D2 tumors. Therefore, D1 and D2 tumors appear to arise by a pathway in which p53 expression is altered, whereas DMBA induction affects a different pathway that does not require such alteration.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1994

Assignment of a locus for mouse lung tumor susceptibility to proximal chromosome 19.

Previous studies have hypothesized that at least three genetic loci contribute to differences in pulmonary adenoma susceptibility between mouse strains A/J and C57BL/6J. One gene that may confer susceptibility to lung tumorigenesis is the Kras protooncogene. To identify other relevant loci involved in this polygenic trait, we determined tumor multiplicity in 56 randomly chosen N-ethyl-N-nitrosourea-treated (A/J x C57BL/6J) N1 x C57BL/6 backcross (AB6N2) progeny and correlated it with genotypes at 77 microsatellite markers spanning the genome. A correlation of lung tumor multiplicity phenotypes with genotypes of microsatellite markers on distal Chromosome (Chr) 6 in the Kras region (Pas1) was confirmed, and a new region on Chr 19 (designated Pas3) was identified that also contributes to susceptibility. Linkage analysis on Chr 19 with 270 AB6N2 mice localized the region flanked by D19Mit42 and D19Mit19 that is most closely associated with lung tumor susceptibility. The Pas3 locus may be an enhancer of the susceptibility locus on Chr 6.

Adenoma↗
PubMed1994

The RB gene locates on chromosome 15 at band 15q13 in the Syrian hamster.

The retinoblastoma susceptibility gene, which encodes a nuclear phosphoprotein (Rb), plays an important role in cell-cycle progression in both normal development and tumorigenesis. Using a Syrian hamster cDNA probe homologous to the human retinoblastoma gene (RB), we have localized the gene to chromosome band 15q13 by conventional in situ hybridization.

Animals↗
PubMed1993

Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.

BACKGROUND: The p53 gene encodes a nuclear phosphoprotein present in low levels in normal human cells. The wild-type form of this protein functions to restrain inappropriate cellular proliferation. Approximately one half of human epithelial ovarian cancers have mutations in the p53 gene and overexpress the mutant protein product. Deletion of one allele of the p53 gene also frequently occurs in these cancers. PURPOSE: We sought to define the spectrum of mutations in the p53 gene in epithelial ovarian cancer with respect to both the specific codons involved and the type of mutations observed. We also examined the frequency of allelic deletion of the p53 gene in cancers containing p53 gene mutations. METHODS: Tissue samples from the epithelial ovarian cancers of 62 patients were obtained during initial laparotomy. Histologic examination was done to ensure that the experimental samples used in this study contained more than 75% cancer cells. Total RNA was extracted from these samples and separately from matched control noncancerous regions of the surgical specimen or white blood cells. The purified RNAs were reverse transcribed to generate cDNA copies of exons 4-10 of the p53 gene. Two rounds of polymerase chain reaction (PCR) were conducted to produce enough template for DNA sequence analysis of the regions of interest within the p53 gene. Dideoxy sequencing of at least two independent productions of each amplified DNA template was done to confirm the validity of the mutations found. Allelic deletions were identified by PCR and gel electrophoretic techniques to examine three polymorphisms within the p53 gene in cancer-normal DNA pairs. RESULTS: We identified 45 mutations in exons 5-8 of the p53 gene, where mutations frequently have been found in other cancer types. An additional mutation was identified in exon 4. Overall, 72% of the mutations were transitions, 24% transversions, and 4% microdeletions. Allelic deletion of the other p53 allele was seen in 67% of ovarian cancers in which a p53 mutation was present. Germ-line p53 mutations were not found in any patients whose cancers had p53 mutations. CONCLUSIONS AND IMPLICATIONS: Like p53 mutations in other types of human cancers, those in epithelial ovarian cancers are diverse and occur frequently in exons 5-8. The predominance of transition mutations suggests that p53 mutations in ovarian cancer arise because of spontaneous errors in DNA synthesis and repair rather than the direct interaction of carcinogens with DNA. These molecular data are consistent with data from epidemiologic studies that have failed to demonstrate a convincing relationship between exposure to environmental carcinogens and the development of ovarian cancer.

Alleles↗
PubMed1993

A deletion unit on chromosome 17q in epithelial ovarian tumors distal to the familial breast/ovarian cancer locus.

Linkage analysis in familial breast and ovarian cancer and studies of allelic deletion in sporadic ovarian tumors have suggested that chromosome 17q may be the location of a gene of importance in ovarian carcinogenesis. We have examined tumor and normal DNA samples from 120 patients with ovarian tumors for allelic deletion at 12 loci on chromosome 17q. Allelic deletion was observed in 64 cases (53%) of which 56 showed loss of heterozygosity at all loci analyzed on 17q. The pattern of allele loss at metastatic sites was consistent with loss of heterozygosity having occurred prior to metastasis. A common region of deletion, defined by 6 cases of invasive epithelial ovarian cancer and a benign serous cystadenoma, spanned 16 cM and was delimited by nm23 and GH. This region is distal to the region on chromosome 17q to which the familial breast/ovarian cancer susceptibility gene has been mapped. The results suggest that a tumor suppressor gene involved in sporadic ovarian carcinogenesis is located on the distal portion of chromosome 17q and is distinct from the gene linked to familial cases.

Alleles↗
PubMed1993

Two classes of mammalian skeletal muscle fibers distinguished by metabolite content.

Phosphorus NMR spectroscopy and HPLC analyses were made on isolated rat and mouse muscles selected for different volume fractions of the major known fiber types. We tested the hypothesis that muscle cell types at rest have intrinsically different contents of PCr, ATP and Pi. The Pi content was low and the PCr and ATP contents were high in muscles with large contents of type 2b and 2a fibers, and vice versa in muscles with large volume fraction of types 1 and 2x fibers. From the profile of these metabolites we could distinguish only two classes of fibers in the murine muscles and predict well the composition of cat muscles. For the first class, types 2a and 2b fibers, the intracellular concentrations were: ATP 8 mM; total Cr 39 mM; PCr 32 mM; Pi 0.8 mM; ADP 8 microM. For the second class, type 1 and 2x fibers, these quantities are: ATP 5 mM; TCr 23 mM; PCr 16 mM; Pi 6 mM; ADP 11 microM. Thus our results establish a new and apparently general criterion upon which to distinguish skeletal muscle cells, one based on the resting content of bioenergetically important metabolites.

Animals↗
PubMed1993

Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice.

Mutations of the p53 tumor suppressor gene are the most common defined genetic alterations seen in a wide variety of human cancers. In contrast, little is known about the importance of the p53 gene in chemically induced tumors of rodents, which are widely used as models for the evaluation of human health risks. In this study we examined 54 methylene chloride-induced and seven spontaneously arising lung tumors from female B6C3F1 mice for losses of heterozygosity (LOH) at markers near the p53 gene on chromosome 11. LOH was detected in seven methylene chloride-induced lung carcinomas by Southern analysis of a restriction fragment length polymorphism and PCR analysis of five simple sequence length polymorphisms. In each case allele loss was observed at all six markers; thus, these chromosomal alterations were likely to have resulted from mitotic nondisjunction. In contrast, LOH was not detected in 20 liver tumors from methylene chloride-treated mice at the Acrb locus, which is tightly linked to the p53 gene on chromosome 11. In addition single strand conformation polymorphism analysis was performed to screen for mutations in the most conserved regions of the p53 gene (exons 5 to 8). Consequently, potential mutations identified by direct sequencing, were only detected in four of the seven tumor samples with LOH, but not in any of the remaining lung tumors. Overexpression of the p53 protein by immunohistochemical staining was detected only in the four tumors that contained p53 point mutations and in a focal area of another tumor. Finally, using a simple sequence length polymorphism within the retinoblastoma tumor suppressor gene, LOH on mouse chromosome 14 was also detected in three lung carcinomas and one liver tumor. Inactivation of p53 and possibly the retinoblastoma tumor suppressor gene appear to be infrequent events in lung and liver tumors from methylene chloride treated mice.

Animals↗
PubMed1993

The effect of metabolic fuel on force production and resting inorganic phosphate levels in mouse skeletal muscle.

1. The effect of different metabolic fuels (glucose, pyruvate and lactate) and no exogenous metabolic fuel on force production was studied in isolated mouse soleus and extensor digitorum longus (EDL) muscles. Force was measured, at 25 degrees C, during isometric tetanic contractions and during contractions with isovelocity stretching and shortening. In parallel experiments, measurements were made of the resting phosphorus metabolite levels using 31P NMR. 2. In soleus muscles, the isometric tetanic force was potentiated with pyruvate (20 mM) as metabolic fuel, compared with glucose (11 mM), by 17.8 +/- 3.6% (mean +/- S.E.M., n = 6). The force was the same with no exogenous metabolic fuel, with glucose, or with lactate as metabolic fuel. The force exerted during shortening was also potentiated by pyruvate and by the same proportion as isometric force. However, during rapid stretching there was no force enhancement with pyruvate. The changes in the force seen with pyruvate are qualitatively similar to those produced when inorganic phosphate (Pi) is lowered in skinned rabbit psoas muscle fibres. 3. We tested whether the Pi content decreased in the presence of pyruvate by measuring resting Pi using 31P NMR spectroscopy. We found that, in soleus muscles, resting Pi was present with glucose and absent with pyruvate as metabolic fuel, and the effect was reversible. 4. EDL muscles produced the same isometric force whether the metabolic fuel was glucose, pyruvate, lactate or if no exogenous metabolic fuel was supplied. EDL muscles already had Pi levels below detectability at rest in glucose. There were no changes in the 31P NMR spectrum with pyruvate as metabolic fuel. 5. It appears therefore that the force potentiation in soleus muscles with pyruvate is due to a lowering of Pi. EDL muscles, which have a very low resting Pi in glucose, therefore have very little potential for force enhancement by this mechanism.

Animals↗
PubMed1993

Neither changes in phosphorus metabolite levels nor myosin isoforms can explain the weakness in aged mouse muscle.

1. The contractile force, phosphorus metabolite levels, intracellular pH and myosin isoforms were compared in isolated soleus and extensor digitorum longus (EDL) muscles from young (6 month old) and aged (28 month old) mice, at 23 degrees C. 2. The isometric force per unit cross-sectional area was significantly lower by 21 +/- 5% in soleus muscles from aged mice compared to those from young mice (mean +/- S.E.M., n = 11 and 9 respectively). 3. The EDL muscle contained twice as much total creatine and phosphocreatine as the soleus, 1.7 times as much ATP, and 0.4 times the inorganic phosphate (Pi) per unit weight. The intracellular pH and free ADP levels were not significantly different between these muscle types. 4. There was no significant difference in resting metabolite levels between young and old EDL or soleus despite the difference in mechanical strength. 5. Examination of the expression of myosin isoforms by non-denaturing gel electrophoresis has shown that the percentage of each isoform does not change with respect to age; thus, if there is an atrophic process occurring, it is not fibre type specific. 6. We have determined that neither the Pi levels nor the intracellular pH can explain the differences seen in muscle strength with age. There is also no correlation between muscle weakness and any of the other metabolites responsible for energy transduction (phosphocreatine, ATP or ADP).

Adenosine Diphosphate↗
PubMed1993

In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice.

Fibroblast cultures were derived from mouse embryos containing either one (p53+/-) or two (p53-/-) inactivated p53 alleles and compared to normal embryo fibroblasts for a number of growth parameters. Early passage p53-deficient embryo fibroblasts (p53-/-) divided faster than normal embryo fibroblasts, achieved higher confluent densities, and had a higher fraction of division-competent cells under conditions of low cell density. Flow cytometry studies of early passage embryo fibroblasts showed that the percent of p53-deficient cells in G0/G1 was lower than in normal cells, consistent with the argument that p53 mediates a G1 block. When p53-deficient and normal cells were passaged for long periods of time, the homozygote (p53-/-) fibroblasts grew at a high rate for over 50 passages and never entered a non-growing senescent phase characteristic of the heterozygote (p53+/-) and normal (p53+/+) cells. The p53-deficient fibroblasts were genetically unstable during passaging, with the p53-/- cells showing a high degree of aneuploidy and the p53+/- cells displaying a moderate level of chromosomal abnormalities by passage 25. Surprisingly, the heterozygote cells lost their single wild type allele very early during culturing and in spite of this loss most heterozygote lines entered into senescence. We conclude that the loss of p53 by itself is insufficient to confer immortality on a cell, but does confer a growth advantage. Taken together, the findings confirm that the absence of p53 promotes genomic instability, which in turn may result in genetic alterations which directly produce immortality.

Animals↗