Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunoglobulin (Ig) variable region (V) genes expressed by IgM chronic lymphocytic leukemia (CLL) B cells display little or no somatic mutations. However, preliminary findings have shown that Ig V genes of IgA and IgG CLLs may be somatically mutated, suggesting that isotype-switched CLLs may represent a "subtype" of the disease. To investigate the degree and nature of somatic mutations and the role of antigen (Ag) in the clonal selection and expansion of isotype-switched CLLs, and to determine whether specific oncogene or tumor suppressor gene mutations are associated with isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3 IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs. These isotype-switched CLL B cells expressed surface HLA-DR, CD19, CD23, and CD5, and displayed no alterations of the bcl-1 and bcl-2 oncogenes and the p53 tumor-suppressor gene. The cDNA VH-D-JH gene sequence was joined with that of the C alpha gene in the B cells of the three IgA CLLs, and with that of the C gamma gene in the IgG CLL B cells. In the IgA/IgG-coexpressing CLL B cells, identical VH-D-JH cDNA sequences were spliced to either C alpha or C gamma genes. In all five CLLs, the pattern of C mu DNA probe hybridization to the digested genomic DNAs was consistent with deletion of the C mu exon from the rearranged Ig gene locus, suggesting that these CLL B cells had undergone DNA switch recombination. In one IgA CLL, the expressed VH gene was unmutated. In all other class-switched CLLs, the Ig VH segment gene was mutated, but the point mutations were not associated with intraclonal diversification. In one IgA and in the IgA/IgG-coexpressing CLL, the nature and distribution of the mutations were consistent with Ag selection. These findings suggest that IgA- and/or IgG-expressing CLLs represent, in their VH gene structure, transformants of B cells at different stages of ontogeny. They also suggest that Ag may play a role in the clonal selection of some of these isotype-switched leukemic cells, but bcl-1 and bcl-2 oncogene rearrangements and p53 tumor suppressor gene mutation are not associated with the pathogenesis of isotype-switched CLLs.
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PMID:Molecular characterization of IgA- and/or IgG-switched chronic lymphocytic leukemia B cells. 905 57

Human keratinocyte immortality is genetically recessive to the normal phenotype of limited replicative lifespan and appears to require the dysfunction of p53 and the cyclin D-Cdk inhibitor p16. In order to test for the inactivation of other candidate replicative lifespan genes in the immortal cells of human tumors, we developed a series of mortal and immortal keratinocyte cultures derived from neoplastic lesions of the head and neck which were amenable to molecular genetic analysis by the loss of heterozygosity (LOH) technique. The results indicate that keratinocyte immortalization in head and neck squamous cell carcinoma (SCC-HN) development involves the inactivation of at least two further pathways to senescence and four in all. Chromosomes 1, 4 and 7 carry genes representing immortality complementation groups C, B and D respectively and immortal keratinocytes showed LOH at either 4q32-q34 between D4S1554 and D4S171 (group B) or 7q31 (group D) but never 1q25 (group C). These results tentatively suggest that the genes responsible for the immortality complementation groups encode proteins on the same pathway to senescence. In addition, all of the immortal keratinocyte lines possessed high levels of telomerase activity and a suppressor of telomerase activity has been mapped to the short arm of chromosome 3p. Five out of eight lines showed LOH at 3p21.2-p21.3, a region which may carry a gene capable of suppressing SCC-HN telomerase. However, alternative mechanisms of telomerase reactivation were also suggested by our results. None of the above genetic alterations were seen in seven senescent neoplastic keratinocyte cultures. Other loci harbouring antiproliferative genes implicated in replicative lifespan showed few or no alterations and any alterations seen were additional to those described above.
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PMID:Evidence for the inactivation of multiple replicative lifespan genes in immortal human squamous cell carcinoma keratinocytes. 915 Mar 62

We investigated the relationship between apoptosis and selective protein expression in brain from rats subjected to 8 (n=10) or 12 min (n=10) of forebrain ischemia and 48 h of reperfusion, and control sham operated (n=2) and normal (n=2). Coronal sections were processed for double staining with DNA fragmentation detection and immunohistochemical staining. In five of ten 8-min ischemic and three of ten 12-min ischemic animals, nearly all dead granule cells within the dentate gyrus exhibited apoptotic morphology. In the remaining animals, no granule cell death was evident. In the pyramidal regions (CA1/2), nearly all dead cells were necrotic with only scattered apoptotic cells present. The immunoreactive expression of wt-p53, p53-response proteins (WAF1, Bax and Gadd45), and a cell cycle protein (cyclin D) were detected and preferentially localized to nuclei of apoptotic granule cells, and were weakly expressed in nuclei of necrotic pyramidal CA1/2 cells. Thus, 48 h after 8 or 12 min of forebrain ischemia in the rat, most pyramidal cells and dentate granule cells undergo distinct cell death pathways of necrosis or apoptosis, respectively. In addition, the selective expression of proteins associated with DNA damage and cell cycle in apoptotic dentate granule cells suggests a role for these proteins in the induction of apoptosis.
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PMID:Granule cell apoptosis and protein expression in hippocampal dentate gyrus after forebrain ischemia in the rat. 926 35

Normal human keratinocytes have a finite replicative lifespan which culminates in senescence. Chromosomal telomere length may act as a mediator of replicative senescence, signalling cell cycle arrest in G1 when one or more telomeres become too short. Telomeric attrition in normal keratinocytes may be due to inadequate levels of telomerase activity and possibly also to oxidative damage. In advanced squamous cell carcinoma replicative senescence breaks down to yield immortal variants, in which several dominantly acting genes are functionally compromised, including p53 and the cyclin D-Cdk4/6 inhibitor CDKN2A/p16. The increased activity of both of these proteins would be expected to contribute to the G1 arrest in senescence and we have shown that levels of p16 are dramatically increased in senescent keratinocytes. In addition, two other genes which control a cell cycle G1 checkpoint independently of p53 and pRb appear dysfunctional. These genes are uncloned but map to chromosome 4q and 7q31.1 and appear to represent senescence complementation groups B and D, respectively. In immortal neoplastic keratinocytes, telomerase is strongly upregulated and there is evidence for a suppressor of the enzyme on the short arm of chromosome 3 mapping to 3p21.2-p21.3. We have also mapped the human telomerase RNA gene to 3q26.3 and found it to be overrepresented or amplified in a proportion of squamous cell tumours and cell lines. These observations may explain why isochromosome 3q is so common in human squamous carcinoma. None of these genetic alterations are seen in carcinomas which senesce and suggest that multiple genetic alterations are required for keratinocyte immortality.
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PMID:The genetic basis of human keratinocyte immortalisation in squamous cell carcinoma development: the role of telomerase reactivation. 928 11

We used double staining histochemistry to investigate the relationship between apoptotic cell death and selective protein expression associated with DNA damage (p53, Bax, MDM2, Gadd45), DNA repair (PCNA) and cell cycle proteins (cyclin A, cyclin D, cdk2, cdk4) in rats (n = 6; control rats, n = 5) subjected to transient (2 h) middle cerebral artery occlusion (MCAo) and 46 h of reperfusion. Few apoptotic cells were detected in the non-ischemic hemisphere of control rats. In ischemic animals, scattered apoptotic cells were present in the ischemic core and clustered apoptotic cells were present and localized to the inner boundary zone of the ischemic core. Proteins were preferentially localized to the cellular cytoplasm of control rats and in the non-ischemic hemisphere of rats subjected to MCAo. However, after MCAo these proteins were expressed and were preferentially localized to nuclei within the ischemic lesion. DNA damage induced proteins (wt-p53 and p53-response proteins) were preferentially expressed within apoptotic cells after ischemia. DNA repair proteins and cell cycle proteins were preferentially expressed within morphologically intact cells and in reversibly damaged cells in the ischemic areas. The selective expression of proteins associated with DNA damage, DNA repair and cell cycle observed in morphologically intact cells, ischemic injured cells and apoptotic cells suggests a differential role for these proteins in cell survival and apoptosis after stroke.
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PMID:Apoptosis and protein expression after focal cerebral ischemia in rat. 931 3

The INK4a tumor suppressor locus encodes p16INK4a, an inhibitor of cyclin D-dependent kinases, and p19ARF, an alternative reading frame protein that also blocks cell proliferation. Surprisingly, mice lacking p19ARF but expressing functional p16INK4a develop tumors early in life. Their embryo fibroblasts (MEFs) do not senesce and are transformed by oncogenic Ha-ras alone. Conversion of ARF+/+ or ARF+/- MEF strains to continuously proliferating cell lines involves loss of either p19ARF or p53. p53-mediated checkpoint control is unperturbed in ARF-null fibroblast strains, whereas p53-negative cell lines are resistant to p19ARF-induced growth arrest. Therefore, INK4a encodes growth inhibitory proteins that act upstream of the retinoblastoma protein and p53. Mutations and deletions targeting this locus in cancer cells are unlikely to be functionally equivalent.
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PMID:Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. 939 58

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.
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PMID:Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma. 940 3

Adenovirus E1A proteins influence cell growth and phenotype through physical interactions with cellular proteins that regulate basic processes such as cell cycle progression, DNA synthesis, and differentiation. p120E4F is a low-abundance cellular transcription factor that represses the adenovirus E4 promoter and is regulated by E1A, through a phosphorylation-induced reduction of its DNA binding activity, to permit activation of the E4 promoter during early infection. To determine the normal biological role of p120E4F, we assessed its ability to influence fibroblast cell growth and transformation. p120E4F suppressed NIH 3T3 fibroblast colony formation but had little effect when coexpressed with E1A and/or activated ras. Cells that overexpressed p120E4F were inhibited in their ability to enter S phase, had elevated levels of the cdk inhibitor p21WAF1, and reduced cyclin D-cdk4/6 kinase activity. The increase of p21WAF1 levels occurred through a p53-independent posttranscriptional mechanism that included a three- to fourfold increase in the half-life of p21WAF1 protein. Coexpression of activated ras with p120E4F stimulated cyclin D1 expression, elevated cyclin D-cdk4/6 kinase activity, and accelerated cell growth. These data suggest an important role for p120E4F in normal cell division and demonstrate that p21WAF1 can be regulated by protein turnover.
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PMID:Adenovirus E1A-regulated transcription factor p120E4F inhibits cell growth and induces the stabilization of the cdk inhibitor p21WAF1. 941 93

Human papillomavirus (HPV) DNA has been detected in approximately 15% of squamous cell carcinomas (SCCs) of the head and neck. Recent studies have shown a predilection of HPV for certain anatomical sites, especially the tonsillar region, with viral DNA identified in approximately 60% of SCCs of the Waldeyer's tonsillar ring. This study was undertaken to determine whether there are differences in morphology or in oncogene expression in SCC of the tonsil with and without detectable HPV DNA. Twenty-two SCCs of the tonsil were analyzed for the presence of HPV DNA by polymerase chain reaction (PCR) using both a consensus primer set (My09/My11) and type-specific primers. Viral transcription was established in both primary and metastatic tumors by RNA in situ hybridization. The morphology of invasive SCC was classified into three subtypes: well keratinized (K-SCC), intermediate keratinized (I-SCC), and poorly keratinized (P-SCC). Expression of p53, pRB, and cyclin D1 (bcl-1) were studied by immunohistochemistry. In these cases (6 K-SCCs, 2 I-SCCs, and 14 P-SCCs), HPV DNA was detected in 14 (64%), with 11 containing HPV-16 (10 P-SCCs, 1 I-SCCs, and 0 K-SCCs) and 1 each containing HPV-33, HPV-59, and an unclassified HPV type (all P-SCCs). Viral oncoprotein E6/E7 transcription was demonstrated in 7 of 7 HPV-16-positive tumors. Cyclin D1 protein overexpression was detected in the majority of HPV-negative tumors (7 of 8 cases), whereas it was minimal or absent in 13 HPV-positive tumors. Overexpression of p53 protein was detected in 3 HPV-negative K-SCCs. In the HPV-positive tumors, fewer malignant cells expressed pRB and the staining was less intense than in the HPV-negative cancers. HPV DNA and E6/E7 expression, especially HPV-16, is detected in the majority of tonsillar SCCs and is almost exclusively associated with a poorly keratinized tumor histology. Decreased expression of cyclin D1, pRB, and p53 in tumors with HPV DNA is consistent with the known effects of the viral oncoproteins on the cellular protein. The morphology of the HPV-positive tumors suggests that HPV may have a predilection for a population of nonkeratinizing squamous cells or that the virally transformed cells inhibit keratinization of the tumor cells. Well keratinized tonsillar SCCs lack HPV DNA and are associated with overexpression of cyclin D1 protein and/or p53, suggesting that mechanisms that alter the cell cycle regulatory proteins, either by interaction with viral oncoproteins or by changes in the cellular proteins themselves, is critical for tumorigenesis of tonsillar SCC.
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PMID:Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. 942 32

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.
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PMID:Role of the p16 tumor suppressor gene in cancer. 950 8


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