The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.

https://jcp.bmj.com/content/jclinpath/55/4/244.full.pdf

The causal relation between human papillomavirus and cervical cancer

For the past decade, cellular oncogenes have attracted the attention of biologists intent on understanding the molecular origins of cancer. As the present decade unfolds, oncogenes are yielding their place at center stage to a second group of actors, the tumor suppressor genes, which promise to teach us equally important lessons about the molecular mechanisms of cancer pathogenesis.

https://science.sciencemag.org/content/sci/254/5035/1138.full.pdf

Tumor suppressor genes.

Papillomavirus infections — a major cause of human cancers

The E7 proteins encoded by the human papillomaviruses (HPVs) associated with anogenital lesions share significant amino acid sequence homology The E7 proteins of these different HPVs were assessed for their ability to form complexes with the retinoblastoma tumor suppressor gene product (p105-RB) Similar to the E7 protein of HPV-16, the E7 proteins of HPV-18, HBV-6b and HPV-11 were found to associate with p105-RB in vitro The E7 proteins of HPV types associated with a high risk of malignant progression (HPV-16 and HPV-18) formed complexes with p105-RB with equal affinities The E7 proteins encoded by HPV types 6b and 11, which are associated with clinical lesions with a lower risk for progression, bound to p105-RB with lower affinities The E7 protein of the bovine papillomavirus type 1 (BPV-1), which does not share structural similarity in the amino terminal region with the HPV E7 proteins, was unable to form a detectable complex with p105-RB The amino acid sequences of the HPV-16 E7 protein involved in complex formation with p105-RB in vitro have been mapped Only a portion of the sequences that are conserved between the HPV E7 proteins and AdE1A were necessary for association with p105-RB Furthermore, the HPV-16 E7-p105-RB complex was detected in an HPV-16-transformed human keratinocyte cell line

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1989.tb08594.x

Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.

Both tumorigenic segregant HeLa X human fibroblast hybrids and tumorigenic HeLa (D98/AH-2) cells can be converted to a non-tumorigenic state following introduction of a single copy of a fibroblast t(X;11) chromosome. The translocated chromosome contains approximately 95% of the 11 chromosome and the q26-qter portion of the X chromosome which contains the hypoxanthine guanine phosphoribosyl transferase (HPRT) gene. Introduction of a human X chromosome has no effect on tumorigenic expression. Suppression of tumorigenicity is relieved by selecting cells which have lost the t(X;11) chromosome by growth in medium containing 6-thioguanine (6-TG). Further, reintroduction of the t(X;11) chromosome into tumorigenic 6TGR cells again suppresses tumorigenicity. Thus, the introduction of a single copy of a human chromosome 11 is sufficient to completely suppress the tumorigenic phenotype of HeLa cells and is suggestive of the presence of tumor-suppressor gene(s) on this chromosome.

Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression of HeLa cells.

Two hypoxanthine phosphoribosyltransferase-deficient human cell lines, D98/AH-2 and HT1080-6TG, were stably transfected with pSV2 gpt, a plasmid containing the selectable marker Escherichia coli xanthine-guanine phosphoribosyl transferase (Eco gpt). Hypoxanthine-aminopterin-thymidine-resistant transformants arose with a frequency of ca. 10(-6) and contained mostly single, but occasionally multiple, copies of the plasmid sequences. These transformants actively express the Eco gpt marker. Single chromosomes from two different HT1080 gpt transformants and one D98 gpt transformant, containing the integrated plasmid sequences, were transferred via microcell-mediated chromosome transfer to hypoxanthine phosphoribosyl transferase-deficient mouse A9 cells. The transferred human chromosomes were identified as 2, 4, and 22, by using a combination of G-11 staining, G-banding, isoenzyme analysis, and in situ hybridization. This system is being used to create a library of interspecies microcell hybrid clones, each clone containing a unique single human chromosome in a mouse background. The complete library will represent the entire human karyotype.

Selective transfer of individual human chromosomes to recipient cells.

Transfection of mammalian cells with genomic DNA and cloned genes is now relatively routine. However, the vast majority of studies have used rodent cells as recipients. Here we describe efficient tran

E S Srivatsan

Papers

Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression of HeLa cells.

Selective transfer of individual human chromosomes to recipient cells.

Plasmid, phage, and genomic DNA-mediated transfer and expression of prokaryotic and eukaryotic genes in cultured human cells