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PubMed1994

The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein.

The two major classes of antigen receptors on murine B lymphocytes, mIgM and mIgD, are both contained in a complex with two additional molecules, Ig-alpha and Ig-beta, which permit signal transduction. Accordingly, early biochemical events after antigen binding to either receptor are similar; biological effects, however, are different. Here, we describe three newly discovered intracellular proteins of 32, 37 and 41 kDa molecular mass, that are non-covalently associated with mIgM, but not with mIgD. These proteins coprecipitate with mIgM in Triton X-100 and Nonidet P-40, but not in digitonin lysates. In addition, mIgM is to some extent associated with 29 and 31 kDa proteins that are predominantly associated with mIgD (see accompanying paper). Amino acid sequencing of p32 and p37 identified p32 as mouse prohibitin; this was corroborated by Western blot analysis with antibodies specific for rat prohibitin. p37 is a newly discovered protein. cDNA clones for both proteins were isolated and sequenced. The deduced amino acid sequence of p32 is identical to that of rat prohibitin. p37 is highly homologous to p32. Since prohibitin was identified as an inhibitor of cell proliferation, its association with mIgM, but not mIgD, could explain the different biological events elicited after engagement of each receptor.

Amino Acid Sequence↗

PubMed1993

Absence of prohibitin gene mutations in human epithelial ovarian tumors.

Multiple loss of heterozygosity (LOH) studies of ovarian cancers have found a high incidence of chromosome 17 loss in these tumors. Several authors have suggested that the region commonly deleted encompasses 17q12-21. In addition, this region has recently been reported to be linked to the familial breast/ovarian cancer syndrome. Recently the human prohibitin gene was mapped to region 17q12-22. Prohibitin causes arrest of DNA synthesis by fibroblast and HeLa cells and prohibitin shows significant homology to a gene (Cc) thought to be important for the regulation of development of Drosophila melanogaster. These findings have led many to consider the prohibitin gene a potential tumor suppressor gene. In addition, sequence analysis of exon 4 of human prohibitin gene revealed mutations in 4 of 23 sporadic breast carcinomas. Because of the proposed function for prohibitin, its alterations in breast cancers, and the fact that its location on 17q falls within a commonly deleted region in ovarian cancers, we have undertaken an analysis of the sequence of prohibitin in epithelial ovarian cancers. Using several polymorphic DNA probes, we identified 20 epithelial ovarian tumors which demonstrated LOH for the region that contains the prohibitin gene. To evaluate whether mutations of prohibitin may be important in ovarian carcinogenesis, we have sequenced exons 4 and 5 of this gene using the technique of genomic amplification with transcript sequencing. Only normal exon 4 and 5 sequence was observed among the 20 tumors screened. These results demonstrate that this region of the prohibitin gene is not mutated in epithelial ovarian cancers and suggest that the prohibitin gene does not play a role in ovarian carcinogenesis. Sequencing of further exons and introns are needed to confirm this latter hypothesis.

Base Sequence↗

PubMed1996

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. Prohibitin genotyping of 22 breast cancer cell lines identified 17 homozygous for the B allele, 5 homozygous for the non-B allele, and no heterozygotes. Four of these cell lines were chosen for further characterization of prohibitin. In cell proliferation assays, the homozygous B breast cancer cell lines (BT-20, SK-BR-3, and MCF7) are all inhibited from traversing the cell cycle following the introduction of wild-type prohibitin transcripts. The cell line homozygous for the alternative non-B allele (BT-549) is not inhibited by transcripts. All of the breast cancer cell lines overexpress the longer form of the prohibitin mRNA (1.9 kb) and the protein. Mutational analysis of the protein-coding region detected no mutations in any of the lines. However, BT-20, SK-BR-3, and MCF7 cells are all mutated in the final 200 bases of the 3' untranslated region (3'UTR) exclusive to the 1.9-kb transcript, but BT-549 cells had no alterations in this region of the 3'UTR. Functional mapping experiments performed in the mutated SK-BR-3 line showed that the wild-type 3'UTR alone is sufficient to inhibit cell cycle progression, indicating that the antiproliferative activity of the prohibitin transcript is localized to this region. Overall, our results show that most (80%) of the cell lines derived from breast tumors have a common prohibitin genotype, suggesting that they belong to the same group of immortalized cells, group B. The results also show that the prohibitin 3'UTR exhibits the characteristics of a trans-acting regulatory RNA (riboregulator), the tumor suppressor activity of which is inactivated by mutation in group B immortalized cells.

Alleles↗

PubMed1996

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. Data presented here show that the expression of a prohibitin mRNA with a long 3' untranslated region (3'UTR) and prohibitin protein is elevated in immortalized cells from all complementation groups. However, all immortalized cells classified in complementation Group B, and no cell lines in any of the other groups, are sensitive to the antiproliferative activity of wild-type prohibitin transcripts. All Group B cells are also homozygous for one of two human prohibitin alleles that are distinguishable by two distinct intron polymorphism restriction sites. Interestingly, sequence analysis of the prohibitin gene from representatives of each of the complementation groups showed that the 3'UTR from Groups A, C, and D matched wild type; however, the sequence from all four Group B cell lines differed from wild type. Functional inhibition assays on truncated wild-type mRNA transcripts as well as 3'UTR specific wild-type and mutated transcripts show that the antiproliferative activity of prohibitin resides, at least in part, in the 3'UTR. These data suggest that the prohibitin 3'UTR may function as a trans-acting regulatory RNA (riboregulator) whose tumor suppressor activity has been inactivated by mutation in Group B cells.

Base Sequence↗

PubMed1997

Prohibitin, a putative negative control element present in Pneumocystis carinii.

Little is known about the molecules involved in the regulation of Pneumocystis carinii replication and development in vitro and in vivo. We describe in this report the identification of a P. carinii gene encoding the P. carinii prohibitin protein. In mammals, the prohibitin gene product has been shown to negatively regulate cell proliferation. A cDNA clone encoding the P. carinii prohibitin gene was isolated from a P. carinii cDNA library and identified on the basis of amino acid sequence homology with prohibitin from mammalian sources. Southern blot analysis confirmed that the prohibitin cDNA clone was of P. carinii origin. Western blot analysis of total P. carinii protein indicated that the prohibitin gene is transcribed and translated in vivo. The P. carinii prohibitin gene was expressed in vivo in human fibroblasts and shown to arrest the cell cycle in the G1 phase. The results obtained suggest a potential role for P. carinii prohibitin in the regulation of P. carinii proliferation and development.

Amino Acid Sequence↗

PubMed1993

Cell cycle activity and expression of prohibitin mRNA.

Prohibitin, a novel intracellular antiproliferative protein, blocks entry into the S phase of the cell division cycle when its mRNA is microinjected into normal fibroblasts or HeLa cells. To learn more about the interaction between prohibitin and the cell cycle, we studied the effect of microinjecting prohibitin mRNA at different points during the transition from G0 to S phase and analyzed prohibitin mRNA and protein levels in different parts of the cell cycle. The antiproliferative activity of microinjected prohibitin mRNA is high in G0/G1 and falls as cells approach S phase. Prohibitin mRNA and protein levels are high in G1, fall with S phase, rise again in G2, and fall in M. Together, these findings suggest that endogenous prohibitin contributes to the control of the G1 to S transition in cycling cells in a complex manner, which involves both a transcriptional and posttranslational mechanism.

Animals↗

PubMed1994

Prohibitin gene is overexpressed but not mutated in rat bladder carcinomas and cell lines.

Prohibitin was isolated as a candidate antiproliferating gene in rat liver cells, and it has been suggested as a tumor suppressor gene in human breast cancer. We investigated the steady state level of prohibitin mRNA in rat bladder cell lines and in rat bladder carcinoma induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and sodium saccharin, as well as the protein level in rat bladder epithelial cells. We also examined the prohibitin gene for mutations using the polymerase chain reaction (PCR) single strand conformation polymorphism (SSCP) and direct sequencing methods. All rat bladder tumors investigated and several cell lines had unexpectedly increased steady state levels of prohibitin mRNA compared with that of normal rat bladder or liver. The prohibitin protein was easily detected by Western blotting in all cell lines regardless of their malignant status or growth rate. However, PCR-SSCP and direct sequencing analysis showed no mutations in the prohibitin gene. These results These results indicate that prohibitin overexpression, but not mutations, may be involved in the early stage of rat bladder carcinogenesis.

Animals↗

PubMed1995

Prohibitin, an antiproliferative protein, is localized to mitochondria.

Prohibitin is a ubiquitously expressed protein with antiproliferative properties. When rat prohibitin tagged with a carboxy-terminal c-Myc epitope was expressed in baby hamster kidney cells the protein was targeted to mitochondria. In immunofluorescence microscopy prohibitin colocalized with a mitochondrial marker E3. Immunoelectron microscopy revealed that prohibitin was associated with the periphery of mitochondria. The amino-terminus of prohibitin shares characteristics of the known mitochondrial import signals, and positioning of the tag at the N-terminus causes accumulation of the protein in the cytoplasm. These findings help to direct functional studies on prohibitin and suggest that a mitochondrial protein may act as a tumor suppressor.

Amino Acid Sequence↗

PubMed1997

Characterization of the plant homologue of prohibitin, a gene associated with antiproliferative activity in mammalian cells.

This report describes the cloning and characterization of a plant cDNA coding for a protein which shows high amino acid sequence similarity with prohibitin, whose gene is associated with antiproliferative activity in mammalian cells. Arabidopsis thaliana and Nicotiana tabacum prohibitin complete cDNAs were isolated, and the expression pattern of prohibitin was examined using polyclonal antibodies raised against the Arabidopsis recombinant prohibitin expressed in Escherichia coli. A single immunoreactive protein was detected in various plant species and in all Arabidopsis organs examined. Subcellular fractionation using tobacco leaves revealed prohibitin in a mitochondrial-enriched fraction. Phylogenetic conservation of prohibitin's amino acid sequence and subcellular localization suggests a similar function in plants, yeast and mammals.

Amino Acid Sequence↗

PubMed1993

Expression of prohibitin in rat seminiferous epithelium.

Subtractive hybridization was used to isolate cDNAs highly expressed in stages IX-XI of the cycle of the seminiferous epithelium in the rat. One of the cloned cDNAs was sequenced and shown to be homologous to a previously described cDNA encoding rat prohibitin. Northern blot analyses showed that 1.9- and 1.2-kb transcripts were present in Sertoli cells whereas 1.5-, 1.2-, and 0.7-kb transcripts were expressed in germ cells. Western blot analyses with anti-peptide antibody to prohibitin revealed only a single 30-kDa protein in testis. Immunocytochemistry demonstrated that prohibitin protein was expressed constitutively in adult Leydig cells and Sertoli cells at all stages. Immunoreactivity of prohibition was very low in preleptotene spermatocytes, very high in leptotene spermatocytes, and very low in zygotene spermatocytes. In pachytene spermatocytes, immunoreactivity was very high in stages VII-XI and was minimal during stages XII and XIV. No protein was detected in spermatogonia and spermatocytes undergoing mitotic and meiotic divisions, respectively. These studies show that the prohibitin gene is expressed differentially in testis. The expression pattern of the prohibitin gene in rat testis appears to correlate with a proposed antiproliferative role of prohibitin.

Aging↗

PubMed1997

Steroidogenic acute regulatory (StAR) protein (p25) and prohibitin (p28) from cultured rat ovarian granulosa cells.

This study has identified and characterized two intracellular proteins (25 and 28 kDa) during ongoing differentiation of rat granulosa cells isolated from preantral and early antral follicles. The identity of p25 was confirmed as the mitochondria associated StAR protein by western blotting analysis. In the culture conditions used, this protein was expressed only when granulosa cells were stimulated with FSH to produce progesterone. It is apparent that the steroidogenic differentiation of granulosa cells affects StAR expression. Amino acid sequence analysis of p28 identified it as prohibitin and was corroborated by western blot analysis with antibodies specific for rat prohibitin. During the ongoing differentiation of granulosa cells there were changes in the expression of p28/prohibitin. Although prohibitin is constitutively expressed in granulosa cells, there is an increase in the more acidic isoform of prohibitin when oestrogen concentrations are raised by increased production or exogenous addition. This increase in this acidic isoform of prohibitin is due to phosphorylation. It is possible that oestrogen induces phosphorylation of prohibitin and, thus, may be involved in the regulation of granulosa cell proliferation and the ontogeny of the ovarian follicle.

Androstenedione↗

PubMed1995

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. All of the immortalized cells expressed elevated levels of prohibitin mRNA and protein. Prohibitin gene structural characterization using Southern and single-strand conformation polymorphism (SSCP) analyses distinguished two alleles. One is cleaved at a polymorphic intronic EcoRI site, exhibits an exon 6-associated SSCP, and is homozygous only in Group B cells. The other is not cleaved at the EcoRI site, has a different exon 6 SSCP pattern, and is homozygous in Groups A, C, and D. In contrast, normal cells are heterozygous for the alleles. These results suggest that prohibitin may play a role as a tumor suppressor in the immortalization of Group B cells.

Alleles↗

PubMed1994

Prohibitin expression during cellular senescence of human diploid fibroblasts.

Prohibitin is an evolutionarily conserved gene postulated to possess tumor suppressor activity and to contribute to the limited lifespan of human diploid fibroblast-like cells. Prohibitin mRNA and protein expression and its ability to become post-translationally modified were determined in human diploid fibroblast-like cells of different in vitro ages. The expression of prohibitin mRNA and protein changes little with increasing in vitro age; however, its protein product is post-synthetically modified in younger but not older cells. These results suggest that prohibitin is similar to the retinoblastoma gene product whose anti-proliferative activity remains active in older cells because it is not post-synthetically modified.

Cell Cycle↗

PubMed1997

The prohibitin family of mitochondrial proteins regulate replicative lifespan.

Cellular senescence is determined by multiple factors, including the genetic regulation of metabolism and responses to endogenous and exogenous stresses [1-4]. Recent studies implicate a limited number of gene products in elongating lifespan in yeast and Caenorhabditis elegans [2-4]; these include the C, elegans gene cik-1, a central regulator of metabolism [5], and yeast RAS2, which controls the response to ultraviolet irradiation and other stresses [3]. Another gene postulated to effect senescence is PHB1, the yeast homologue of prohibitin [3], a rodent gene initially identified as a potential regulator of growth arrest and tumour suppressor [6-8]. Highly conserved prohibitin homologues have been identified in mammals [9], Drosophila [10], C. elegans [9], plants [11] and yeast. A second mammalian gene, encoding BAP37, a protein with sequence similarity to prohibitin, is thought to be involved in lymphocyte function [9]. Here, we show that the nuclear-encoded mammalian prohibitin and BAP37 proteins are present in mitochondria, are co-expressed, and interact physically with each other. Deletion of the Saccharomyces cerevisiae homologues, PHB1 and PHB2, results in a decreased replicative lifespan and a defect in mitochondrial membrane potential. Our observations highlight the relationship between the metabolic efficiency of cells and the ageing process, and provide evidence for its evolutionary conservation.

Amino Acid Sequence↗

PubMed1997

Partial cloning of prohibitin cDNA from canine, feline, bovine, equine, and rabbit liver mRNA by RT-PCR.

Prohibitin is the protein which has an inhibitory function in cell growth, and its gene is suggested to be one of putative tumor suppressor genes. In this report, we described a partial cloning of prohibitin cDNAs from canine, feline, bovine, equine, and rabbit liver mRNAs by RT-PCR, and their homology analysis. The sequences of these RT-PCR products were compared with each other as well as those reported for human and rat. The homology in this region of prohibitin cDNA was approximately 90%, and the amino acid sequence of each RT-PCR product shared more than 95% identity. Therefore, it is concluded that all the RT-PCR products are a part of prohibitin cDNA of each animal.

Amino Acid Sequence↗

PubMedDate not supplied

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. Prohibitin's 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.

Aging↗

PubMedDate not supplied

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.

Animals↗

PubMed1991

Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells.

Genes that act inside the cell to negatively regulate proliferation are of great interest because of their implications for such processes as development and cancer, but these genes have been difficult to clone. This report details the cloning and analysis of cDNA for prohibitin, a novel mammalian antiproliferative protein. Microinjection of synthetic prohibitin mRNA blocks entry into S phase in both normal fibroblasts and HeLa cells. Microinjection of an antisense oligonucleotide stimulates entry into S phase. By sequence comparison, the prohibitin gene appears to be the mammalian analog of Cc, a Drosophila gene that is vital for normal development.

Amino Acid Sequence↗