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1.
Am J Pathol ; 153(1): 183-90, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9665479

ABSTRACT

The repertoire of distinct CD44 protein isoforms is generated by means of alternative pre-mRNA splicing of 10 variable exons located in the central region of the CD44 gene. We have used human breast ductal carcinoma as a model to identify two alternative splicing pathways of the CD44 pre-mRNA variable region that account for the generation of all of the CD44 isoforms described in breast tissue. An alternative splicing pathway that reflects inclusion of variable exons in a gradual 3'-to-5' fashion is evidenced in breast ductal carcinoma and its lymph node metastases. This pathway is compatible with a mechanism that generates the standard form of CD44 (devoid of variable exons) and is distinguishable from an alternative splicing pathway that involves exclusively variant exon 3 and is observable in both normal and carcinoma breast tissue. We show that both pathways are detectable in the same cell type in the breast and provide a speculative model by which these splicing routes could take place.


Subject(s)
Alternative Splicing , Breast Neoplasms/immunology , Breast/immunology , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Cloning, Molecular , Female , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Immunoenzyme Techniques , Polymerase Chain Reaction , Transcription, Genetic
2.
J Neuropathol Exp Neurol ; 55(2): 144-9, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8786372

ABSTRACT

p52 protein accumulation in JC virus (JCV)-infected cells of progressive multifocal leukoencephalopathy (PML) has been previously shown. Since many viral proteins are known to bind and stabilize p53, we are addressing the question of whether p53 protein accumulation in PML is the result of its sequestration by JCV and not the outcome of a p53 gene mutation which would prolong its half-life. We have investigated the status of the p53 gene in frozen autopsy brain samples from five PML patients. After isolating genomic DNA, p53 gene exons 2 through 9 were amplified and sequenced. No discrepancies were found in the DNA sequences of exons 2 through 9 and their intron/exon barriers when compared to those published for wild-type p53. On the other hand, dual (p53/DNA) flow cytometry analysis revealed p53 expression above that of the isotypic controls for each case. No aneuploid populations could be identified, however, which seems at odds with the aneuploid status normally associated with mutation-induced p53 dysfunction. These results indicate that the p53 gene harbors no mutations in PML and provide further evidence of p53 protein accumulation in this condition. Since p53 protein buildup in JCV-infected cells is not the consequence of a mutagenic interaction between JCV and the cell genome, we propose instead that p53 accumulation results from its binding and stabilization by JCV T protein.


Subject(s)
Leukoencephalopathy, Progressive Multifocal/pathology , Tumor Suppressor Protein p53/analysis , Base Sequence , DNA Probes , Flow Cytometry , Humans , In Situ Hybridization , Molecular Sequence Data
3.
J Pathol ; 177(4): 363-8, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8568590

ABSTRACT

Cluster of differentiation 44 (CD44) encompasses a polymorphic family of cell membrane glycoproteins involved in the mechanism of tumour invasion and metastasis. Since non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) display very different rates of progression, a significant discrepancy in their CD44 expression profiles is to be expected. An immunohistochemical study was undertaken on the expression of standard CD44 (CD44s) and the variant isoforms containing the domains encoded by variant exon 3 (CD44v3) or variant exon 6 (CD44v6) in paraffin-embedded bronchial biopsy specimens from 32 NSCLC cases and 11 SCLC cases. An absolute lack of immunoreactivity for CD44s, CD44v3, and CD44v6 was obtained in every case of SCLC, whereas 28 of the 32 NSCLC cases showed a positive immunoreaction for at least one of the three epitopes investigated. In conclusion, the occurrence of standard and variant CD44 isoforms in NSCLC and their absence in SCLC suggest the possibility that CD44 is in some way instrumental in conditioning the biological behaviour of NSCLC, but not of SCLC, whose metastatic cascade would be set in motion by the activation of hitherto unidentified, CD44-independent pathways.


Subject(s)
Carcinoma, Non-Small-Cell Lung/chemistry , Carcinoma, Small Cell/chemistry , Hyaluronan Receptors/analysis , Lung Neoplasms/chemistry , Neoplasm Proteins/analysis , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Immunoenzyme Techniques , Male , Middle Aged
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