To date cyclin D1/parathyroid adenomatosis gene 1 (PRAD1) together with the MEN1 is the only gene with an established role in the development of sporadic (nonfamilial) parathyroid adenomas.
The cyclin D1/parathyroid adenomatosis gene 1 oncogene
The cyclin D1/PRAD1 gene was identified as a parathyroid oncogene on chromosome 11 q13, clonally activated in a subset of parathyroid adenomas by tumor-specific DNA rearrangement with the parathyroid hormone (PTH) gene locus. The rearrangement separated the 5′ regulatory region and the noncoding exon 1 of the PTH gene from its coding exons, with different, non-PTH DNA, placed adjacent to each PTH gene section with a pericentromeric inversion of chromosome 11, bringing the PRAD1 (normally on 11q) under the control of the PTH gene 5′ flanking region (on 11 p) (Fig. 4). (The tumor cells has one intact PTH gene that accounted for expression of PTH by the tumor). This rearrangement causes transcriptional activation and overexpression of the PRAD1 gene (Fig. 5). Consequent to its discovery as a parathyroid oncogene, cyclin D1 has become established as a major and broad contributor to other neoplasia such as breast cancer, multiple mieloma, B-cell lymphomas and others. The cyclin D1 gene encodes a 295 amino acid protein homologous to members of cyclin class of proteins. Cyclins play an important role in the regulation of cell cycle progression, and human cyclins have been grouped in different types according to sequence similarity. The C, D and E type cy- clins appear to be G1 cyclins which regulate the progression throught G1 phase and the G1-S transition, determining whether initiation of a new cell cycle occurs. During G1, cyclin D1 complexes with and activates its kinase partner, cyclin-dependent kinase (CDK) CDK4 or CDK6, depending on tissue type. The activated kinase is involved in the phosphorylation and inactivation of retinoblastoma protein (pRb), determining progression toward S-phase. It is thought, therefore, that overexpression or deregulated expression of cyclin D1 could quite conceivably accelerate the cell’s progress through G1 into S phase, bypassing normal regulatory controls in committing to divide, and also be well tolerated by the cell during the remainder of the cycle. Such a mechanism would provide an appealing explanation for the benign nature of parathyroid adenomas, because it could yield excessive cellular proliferation without necessarily conferring the phenotype of invasiveness or metastasis to the tumor cell.
Functional studies have shown that the effects of cyclin D1 on proliferation are mediated throught its ability to phosphorylate and thereby inactivate pRb. It appears that the cyclin D1- CDK4/6-p16-Rb pathway has become aberrant in virtually every human tumor. In recent years, our understanding of the mechanisms by which cyclins regulate proliferation and differentiation has evolved and accumulating evidence suggests that, in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 regulates activity of transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tu- morigenesis.
Figure 4 – Schematic diagram illustrating the pericentromeric chromosomal inversion that occurred in parathyroid adenomas. The PTH gene’s 5′-regulatory region is rearranged upstream of cyclin D1/PRAD1, and the cyclin D1 gene is overexpressed by the PTH promoter.
In different parathyroid adenomas, the 11 q 13 chromosome breakpoint can be positioned within 1-2 kb of cyclin D1, or as much 300 kb upstream and further. Because these gene break points could vary widely they can be missed with traditional approaches (i.e. Southern blotting) and we may not have therefore a precise percentage of the rearrangements in parathyroid neoplasia. The best estimate to date of the frequency of the involvement of cyclin D1 expression come from assessment of expression at the protein level. Immunohistochemical studies have shown a cyclin D1 overexpression in 20-40% of parathyroid adenomas.
To define the role of cyclin D1 in parathyroid neoplasia, and to investigate the relationship between proliferative and hormonal regulatory abnormalities in this disease, a transgenic mouse model with parathyroid-targeted overexpression of cyclin D1 has been developed. These mice carry a transgene in which the cyclin D1 gene is placed adiacent to a 5.2 kb fragment of the PTH regulatory region, thereby mimicking the DNA rearrangement and cyclin D1 overexpression observed in human tumors. The phenotype of these mice was very similar to that of patients with PHPT. The parathyroid glands were hyper- cellular with increased proliferative rates and, in some cases, they develop parathyroid adenomas. PTH-cyclin D1 mice developed not only abnormal parathyroid cell proliferation but also biochemical hyperparathyroidism, with the characteristic bone abnormalities. The transgenic mice show decreased bone volume and increased bone turnover, with increased numbers of osteoclasts and reduced bone formation. This high turnover phenotype has marked similarities with the human bone under the influence of PTH excess. Notably, these mice had an increase in the PTH-calcium set point, similar to that observed in the human disease. Thus, cyclin D1 may not only control cellular proliferation but also contribute to abnormal hormonal secretion. In a recent article, the same authors, using this animal model, analyzed the temporal sequences of proliferative and set point abnormalities that occur in parathyroid tumorigenesis. They demonstrate that abnormal parathyroid proliferation regularly precedes dysregulation of the calcium-PTH axis, supporting the concept that disturbed parathyroid proliferation is the crucial primary initiator leading to the development of the biochemical phenotype of PHPT. In addition, they observed that decreased expression of the CASR in the parathyroid glands occurs several months before development of biochemical PHPT, suggesting that decreased CASR may not be sufficient to cause PTH dysregula- tion in this animal model of PHPT. In contrast, mice that exhibit a similarly decreased level of CASR but, as a result of a germline heterozygous knockout of the CASR gene, demonstrate a clear rightward shift in the set point curve with hypercalcemia and inappropriate PTH level. It is possible, that the stage of development at which alteration is imposed (embryon- ic/germline vs. postnatal/acquired) may lead to different phenotype. These data suggest that the typical reduction in CASR expression in parathyroid adenoma may not be the only determinant of the altered set point of the tumor cells. It has been also hypothesized that somatic mutations that inactivate the CASR gene play an important role in parathyroid tumorigenesis. However, CASR mutations are not observed in sporadic parathyroid adenomas. It has been suggested that other factors such as functional activity of the CASR or oscillations of intracellular Ca2+ may play a role in the CASR-mediat- ed signaling. Furthermore, the primary cyclin D1 abnormalities, may have a more direct role in regulating the expression of CASR.
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Figure 5 – Schematic diagram of the molecular structure of the PTH/ PRAD1 DNA rearrangement and its functional consequences. The sign X represents the chromosomal breakpoint between the PTH gene regulatory region, plus PTH 5′ region.