Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 3' untranslated region mutations.

The evolutionarily conserved prohibitin gene is located on human chromosome 17q21, and two alleles have been identified. Our previous studies characterizing prohibitin in immortalized cells, classified into four complementation groups (A-D) based on the ability of whole-cell hybrids to become senescent, have suggested that it has tumor suppressor activity in group B cells. Only the cell lines assigned to group B are sensitive to the antiproliferative activity of prohibitin, and all are homozygous for an allele designated B because of its exclusive association with this group.

The 3' untranslated region of prohibitin and cellular immortalization.

We have been studying the role of the evolutionarily conserved prohibitin gene in cellular immortalization and tumor suppression. Immortalized human cells are classified into four complementation groups (A, B, C, and D) based on the ability of fusion hybrids to become senescent. The present study expands our preliminary evidence showing that the antiproliferative activity of prohibitin is only effective in immortalized Group B cells and normal cells.

Prohibitin and the senescent phenotype.

Prohibitin is an evolutionarily conserved gene that has antiproliferative activity, is ubiquitously expressed, and appears to be essential for cell survival. The gene codes for a 30 kD, post-synthetically modified protein located primarily in the mitochondria. It functionally inhibits cell cycle traverse and DNA synthesis, but its mechanism of action is presently unknown.

Regions of evolutionary conservation between the rat and human prohibitin-encoding genes.

We have analyzed and compared the 5' promoter region, the intron structure and the exon-intron flanking sequences in the rat and human prohibitin-encoding genes (PHB). Comparative analysis of a 350-nt region immediately 5' to and including the first exon identifies eight highly conserved regions, four of which correspond to binding sites for known transcriptional control proteins (CCAAT box, 'SV40' site and two Sp1 sites). The promoter lacks a TATA box.

Prohibitin antiproliferative activity and lack of heterozygosity in immortalized cell lines.

Experiments were performed to determine whether prohibitin, an evolutionarily conserved gene with antiproliferative activity, has a role in cellular immortalization. A cell proliferation assay was used to examine one human cell line from each of four established immortal complementation groups, termed A, B, C, and D, and a normal human diploid fibroblast line. Only normal and Group B cells were inhibited from traversing the cell cycle after introduction of wild-type prohibitin transcript.