The McCune-Albright syndrome: the whys and wherefores of abnormal signal transduction

Article Abstract:

McCune-Albright syndrome is a triad of bone, skin, and hormonal abnormalities. Upon X-ray, one or more bones appear to have a cyst, but in actuality, the round lesion is a solid fibrous mass. Numerous cafe au lait spots appear on the skin; these have a rough edge, which distinguishes them from the smoother lesions seen in neurofibromatosis. Last in the triad, patients have multiple endocrine abnormalities, which may include precocious puberty. In contrast with multiple endocrine neoplasia, however, there is no observed increase in hormones in the blood. The defect in McCune-Albright syndrome seems to be located in the hormone receptors themselves. Many, but not all, hormone receptors on the cell surface are connected with a complex consisting of several distinct proteins. This protein complex catalyzes the synthesis of cyclic AMP when the receptor portion of the complex on the outside of the cell binds a hormone molecule. This cyclic AMP then starts a chain of events which determines various aspects of the cell's metabolism and action. A portion of this receptor complex is designed to inactivate the receptor after it has been stimulated. Some of the proteins in this large complex are called G proteins for their ability to bind guanine nucleotide. The G proteins belong to a family of more than 16 members. In the December 12, 1991 issue of The New England Journal of Medicine, researchers present data indicating that a defect in one of the G proteins may be responsible for McCune-Albright syndrome. This particular G protein, Gs-alpha, is part of the Gs trimer that undergoes a continuous cycle of regulation. When the receptor is stimulated by a hormone or a drug, the Gs-alpha chain is released, promoting the enzymatic synthesis of cyclic AMP. The cycle of regulation is complete when the Gs-alpha becomes reassociated with a molecule of guanosine diphosphate, which promotes the return of Gs-alpha back to its position in the Gs complex of three proteins. The return of the Gs-alpha chain inactivates the receptor complex until the next hormone molecule arrives. If a mutation in this Gs-alpha molecule interferes with the ability of this molecule to inactivate the receptor, then the response will continue whether hormone is present or not. As a result, symptoms appear that resemble the symptoms that accompany excess hormone. (Consumer Summary produced by Reliance Medical Information, Inc.)

G proteins, Dysplasia

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Signaling pathways and c-fos transcriptional response - links to inherited diseases

Article Abstract:

Diseases involving abnormal cell growth, such as fibrous dysplasia, may be better understood by studying chemicals outside of cells that affect gene expression. Fibrous dysplasia is the abnormal growth of bone marrow cells and it can lead to bone cancer. A 1995 study found a high rate of expression of the c-fos gene in patients with fibrous dysplasia. This increase in gene expression is triggered by chemicals outside of cells. Concentrations of AMP outside of cells increases the activity of the enzyme protein kinase A inside, which in turn increases the expression of genes such as c-fos. It would be useful to identify other chemicals that promote cancer gene expression, and to identify other genes that are highly expressed in abnormal cells.

Gene expression

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Increased expression of the c-fos proto-oncogene in bone from patients with fibrous dysplasia

Article Abstract:

A high level of expression of the c-fos proto-oncogene may play a crucial role in bone cancer development in patients with fibrous dysplasia. Fibrous dysplasia is the abnormal growth of cells in the bone marrow. Among patients with this disease, 0.5% develop bone cancer. The abnormal bone marrow cells from 8 fibrous dysplasia patients showed a high level of c-fos gene expression. However, normal marrow cells from two of these patients and marrow cells from two healthy subjects showed much lower c-fos expression. Among eight patients with bone disorders other than fibrous dysplasia, c-fos expression was low or undetected. Thus an elevated expression of the gene occurs specifically in patients with fibrous dysplasia.

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