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Biomedical subjects

C J Larsen

Publications and source records attributed to C J Larsen.

At least 37 records · Page 2Linked to original sources
PubMed1998

The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer.

The p16IN4/CDKN2/MTS1 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16INK4a, which regulates retinoblastoma protein-dependent G1 arrest, and a cell cycle inhibitor designated p19ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16INK4a has been described as a frequent event in lung cancer, the current function of p19ARF is still poorly understood. We have examined the expression of the human p19ARF (hp19ARF) protein in a large series of lung cancers using immunohistochemistry and showed that the protein was more frequently lost in high-grade neuroendocrine (NE) lung tumors (large cell NE carcinoma and small cell lung carcinoma; 51 of 78, 65%) than it was in non-small cell lung cancer (25 of 101, 25%). No deleterious mutation was found in exons 1beta and 2 of hp19ARF in those NE tumors with negative immunoreactivity, and a beta transcript was detected in the majority of them. Concomitant absence of hp19ARF and retinoblastoma proteins was frequently detected in high-grade NE lung tumors, whereas no relationship could be found between the status of hp19ARF and p53 proteins in those tumors. These results are consistent with an alternative growth suppressor function for hp19ARF in NE lung cancer that is distinct from that of p16INK4a. Moreover, the frequent uncoupling between the beta transcript and the hp19ARF protein suggests a novel mechanism of inactivation at the translational level.

Carcinoma, Small Cell↗
PubMed1998

[When p19ARF finds a partner or new "dangerous liaisons"].

In man, the MTS1 (multiple tumor suppressor 1) locus has been located on chromosome band 9p21 and encodes two unrelated genes, p16INK4a and p19ARF that both act, through different mechanisms, as cell proliferation inhibitors. The inhibitory mechanism of p19ARF has begun to be elucidated by the finding that the protein has the ability to bind the mdm2 oncoprotein. mdm2 is implicated in the degradation of p53 and its functional inactivation. While this result provides an opportunity for understanding the tumor suppression role of p19ARF, it allows to define a new cell cycle regulatory pathway, the p19ARF-p53 pathway. In this respect, MTS1 is unique in its ability to control two crucial pathways that regulate the cell cycle. For this reason, it will be crucial to investigate the status of p19ARF in a variety human tumors.

Animals↗
PubMed1998

[Alternative protein p19ARF: a genuine tumor suppressor gene].

The p16INK4a gene located in the MTS1 (multiple tumor suppressor 1) locus encodes two proteins, p16INK4a and p19ARF, which are structurally unrelated but functionally similar as both inhibit cell cycle progression. In this review, we report and comment new data obtained from mice knockouted for p19ARF without interfering with the expression of p16INK4a. This results in the rapid occurrence of a spectrum of tumors. These data establish that p19ARF is a genuine tumor suppressor protein and raise the questions of the relationship between the two proteins and their respective importance in malignancies.

Animals↗
PubMed1997

The human protein p19ARF is not detected in hemopoietic human cell lines that abundantly express the alternative beta transcript of the p16INK4a/MTS1 gene.

The p16/MTS1/CDKN2 gene on human chromosome band 9p21 encodes two unrelated proteins: p16INK4a, a specific inhibitor of the cyclin D-dependent kinases CKD4 and CDK6, and the structurally unrelated p19ARF protein that arrests cell growth in G1/S and also in G2/M. By use of polyclonal antibodies, the human p19ARF (hp19ARF) protein has been identified in the nucleus of various cells including normal cultured fibroblasts. The level of this protein did not fluctuate throughout the cell cycle and was more elevated in fibroblasts with limited or arrested growth, suggesting that p19ARF accumulated in presenescent or senescent cells. Interestingly, hp19ARF was not detected in several hemopoietic tumor cell lines (mainly of B-type lymphoid origin) that expressed abundant amounts of the p16beta transcript. This finding indicates that in certain tumors, the expression of hp19ARF RNA and protein may be uncoupled. Furthermore, it suggests that disruption of a translational mechanism may be involved in the inactivation of hp19ARF.

Animals↗
PubMed1997

Contribution of the dual coding capacity of the p16INK4a/MTS1/CDKN2 locus to human malignancies.

During the three last years, the so-called p16 locus on human chromosome band 9p21 has been increasingly implicated in different cancers by a variety of alterations abolishing both copies of the p16INK4a/MTS1/CDKN2 gene and the adjacent p15INK4b gene, two members of a family of specific inhibitors of the cyclin D 1-3-CDK4/6 complexes that control cell cycle progression of the G1 to S phase. While these properties are characteristic of tumor suppressor genes, abundant experimental data have clearly identified a link between the loss of function of p16INK4a and tumorigenic processes. The role of p15INK4b alterations in the onset of natural and experimental tumors is less obvious. New light may be shed on the role of the p16 locus in tumor development by the recent finding that an alternative transcript from the p16INK4a gene encodes p19ARF, a negative regulator of cell cycle progression which is unrelated to p16 and p15 and does not act by binding any CDK. Hence, this protein appears to be an element of a novel negative cell cycle control mechanism, whose impairing might be involved in tumorigenesis.

Amino Acid Sequence↗
PubMed1997

[Tribulations of the p16/MTS1/CDKN2 tumor gene suppressor: a continuing saga].

Since its recent discovery on chromosome 9p21 band, the p16INK4a/MTS1/CDKN2 gene has been reported as one of the most frequently impaired tumor suppressor genes (ranking second after p53) in a variety of malignancies, including acute lymphoblastic leukemias. In fact, the situation is likely to be more complex than expected: the gene has a very unusual status in that sense that it encodes two structurally unrelated but functionally similar proteins, p16INK4a and p19ARF. In this minireview, the present status of the gene is examined.

Animals↗
PubMed1997

FISH analysis of translocations involving the short arm of chromosome 9 in lymphoid malignancies.

Deletion of the short arm of chromosome 9 (9p), resulting in the loss of the p16INK4a/MTS1 gene, now called CDKN2, has been found to occur frequently in acute lymphoblastic leukemia, even in the absence of a microscopically visible deletion. In this study, we have used YAC probes encompassing the CDKN2 locus to analyze by fluorescence in situ hybridization patients with leukemia and lymphoma and translocations involving 9p in order to establish the CDKN2 status in relation to the karyotype. We found that, in leukemic cells exhibiting loss of heterozygosity at the CDKN2 locus, the deleted allele was from the cytogenetically normal chromosome 9, whereas the other allele was located on a rearranged chromosome. This finding suggests that CDKN2 gene loss is nonrandomly associated with 9p translocation in lymphoid proliferations. Genes Chromosom.

Adult↗
PubMed1996

Inactivation of the P16INK4/MTS1 gene by a chromosome translocation t(9;14)(p21-22;q11) in an acute lymphoblastic leukemia of B-cell type.

We have reported previously a preliminary study of a t(9;14)(p21-22; q11) in B-cell acute lymphoblastic leukemia. This translocation had rearranged the TCRA/D locus on chromosome band 14q11 and the locus encoding the tumor suppressor gene P16INK4/MTS1 (P16) on band 9p21 (D. Duro et al., Oncogene, 11: 21-29, 1995). In the present report, the breakpoints were precisely localized on each chromosome partner. On the 14q- derivative, the sequence derived from chromosome 9 was interrupted at 1.0 kb upstream of the first exon of P16, close to a consensus recombination heptamer, CACTGTG. In addition, the chromosome 14 breakpoint was localized at the end of the TCRD2 (delta 2) segment, and 22 residues with unknown origin were present at the translocation junction. On the 9p+ derivative, chromosome 9 sequences were in continuity with those displaced onto chromosome 14, and the 14q11 breakpoint was located within TCRJA29 segment. These features are consistent with aberrant activity of the TCR gene recombinase complex. Although all three coding exons of P16 were displaced onto the chromosome 14q-derivative, no P16 transcript was detected in the leukemic cells. Because the region spanning the P16 exon 1 was not inactivated by methylation and because the other P16 allele was deleted, the implication is that the chromosome breakpoint was likely to disrupt regulatory elements involved in the normal expression of the gene. As a whole, then, our results show that translocations affecting band 9p21 can participate to the inactivation of P16, thus justifying a systematic survey of translocations of the 9p21 band in acute lymphoblastic leukemia.

Base Sequence↗
PubMed1996

The I protein of the heterogeneous nuclear ribonucleoprotein complex is a novel dog nuclear autoantigen.

In eukaryotic cells, heterogeneous nuclear RNA is associated with a set of abundant nuclear proteins to form complex ribonucleoprotein structures (hnRNP). Autoantibodies to hnRNP G protein have been previously reported in German shepherd dogs with lupus-like syndrome. In the present study, we describe the characterization of a novel antigen recognized by a serum from a schnauzer dog with a non-erosive polyarthritis. The autoantibodies give, by indirect immunofluorescence, a nuclear pattern with staining close to one of the nucleoli. Immunoblotting and immunoprecipitation data reveal that the autoantigens are in fact two closely related basic proteins (average pI 8.7) with apparent molecular weights of 56 kDa (p56) and 59 kDa (p59). The results of immunoprecipitation with anti-hnRNP antibodies and DNA affinity column chromatography strongly suggest that these autoantigens correspond to hnRNP I proteins. This point was confirmed by cloning and sequencing a cDNA clone encoding the complete sequence of the antigens. In addition, we found that anti-hnRNP I antibodies preferentially stain certain loops of the Pleurodeles waltl lampbruch chromosomes. These data, added to previous ones on anti-p43/hnRNP G protein in German shepherd dogs with lupus-like syndrome, confirm the interest of this category of antibodies to hnRNP proteins in autoimmune disorders.

Amino Acid Sequence↗