Robert T. Dell'Orco

Prohibitin: Potential role in senescence, development, and tumor suppression

Prohibitin is an evolutionarily conserved gene with homologues found in organisms ranging from yeast to man. In man the gene is located on chromosome 17 at q21. The deduced amino acid sequences of the protein products from mouse and rat are identical; and these differ from the human protein sequence by a single conserved amino acid. Prohibitin has antiproliferative activity and available data suggest a role in such diverse processes as normal cell cycle regulation, replicative senescence, cellular immortalization, and the development of sporadic breast tumors. Although its functional activity is presently unknown, the 30,000-Da protein has been located in the inner membrane of mitochondria, where it is postsynthetically modified, as well as on the plasma membrane of B cells, where it is associated with the IgM receptor. Prohibitins evolutionary conservation and ubiquitous expression indicate that it is a fundamentally important gene; and current data suggest a functional role in such dissimilar processes as development, senescence, and tumor suppression.

Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver

Studies of chromosome loss in inherited cancers, of fusions between proliferating and quiescent cells, and of microinjection of RNA from quiescent cells into proliferation competent cells have all provided evidence for antiproliferative genes in mammalian cells. In this report, we describe a partial cDNA clone isolated on the basis of its preferential hybridization to RNA from normal versus regenerating rat liver. The corresponding mRNA, enriched by hybrid selection, was microinjected into normal human diploid fibroblasts in cell culture, resulting in a 53% decrease in the fraction of nuclei incorporating tritiated thymidine. This mRNA is 2 kb in size and is expressed in eight tissues examined.

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. Prohibitin is proposed to be a member of a new class of tumor suppressor genes whose inhibitory activity plays a role in the dominant senescent phenotype. Its involvement in senescence has been postulated from results obtained from such diverse systems as yeast and human diploid fibroblasts. Additional data show that prohibitin is involved in one of the limited number of pathways that results in the loss of the senescent phenotype and leads to cellular immortalization. Its involvement, however, occurs downstream in the pathway and is postulated to be part of the lost tumor suppressor activities associated with tumorigenicity.