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Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.
Estrogen plays an important role in regulating cell proliferation in a tissue-specific manner. Estrogen shortage induces aging and atrophic changes in a number of estrogen-responsive organs including uterus, breast and brain. On the other hand, increased supplies and actions of estrogen have been implicated as playing a pivotal role in stimulating cell proliferation during tumorigenesis and progression of breast cancer and endometrial cancer 1. Although the mechanisms by which estrogen regulates cell proliferation and aging remain to be fully understood, several genes that control cell proliferation have been shown to be downstream targets of estrogen action 2. Among these genes, the proto-oncogene c-myc has been reported as a direct target gene of estrogen in estrogen receptor-positive cells 3. Recently, studies have shown that estrogen stimulates the activity of the enzyme telomerase and gene expression of telomerase reverse transcriptase (TERT) in cancer cell cultures (reviewed in 4, 5). Telomerase is required to maintain the structures of chromosomal ends (telomeres) for continuous cell division in human embryonic development and cancer (reviewed in 6, 7, 8). Telomerase interacts with telomeric DNA and other telomere binding proteins, catalyzing telomeric DNA reverse transcription to lengthen telomeres and capping the telomere ends 9, 10, 11. In the absence of telomerase, telomeres shorten, and short telomeres trigger cell senescence and apoptosis at a threshold of telomere length, thereby limiting cell proliferative lifespan. While telomerase is consistently repressed during cell differentiation to mature somatic cells in man, telomerase is active in a number of somatic tissues in mice. However, little is known as to how telomerase activity is regulated in vivo under physiological conditions.
The complete study
http://www.nature.com/cr/journal/v18/n11/full/cr2008291a.html
Estrogen plays an important role in regulating cell proliferation in a tissue-specific manner. Estrogen shortage induces aging and atrophic changes in a number of estrogen-responsive organs including uterus, breast and brain. On the other hand, increased supplies and actions of estrogen have been implicated as playing a pivotal role in stimulating cell proliferation during tumorigenesis and progression of breast cancer and endometrial cancer 1. Although the mechanisms by which estrogen regulates cell proliferation and aging remain to be fully understood, several genes that control cell proliferation have been shown to be downstream targets of estrogen action 2. Among these genes, the proto-oncogene c-myc has been reported as a direct target gene of estrogen in estrogen receptor-positive cells 3. Recently, studies have shown that estrogen stimulates the activity of the enzyme telomerase and gene expression of telomerase reverse transcriptase (TERT) in cancer cell cultures (reviewed in 4, 5). Telomerase is required to maintain the structures of chromosomal ends (telomeres) for continuous cell division in human embryonic development and cancer (reviewed in 6, 7, 8). Telomerase interacts with telomeric DNA and other telomere binding proteins, catalyzing telomeric DNA reverse transcription to lengthen telomeres and capping the telomere ends 9, 10, 11. In the absence of telomerase, telomeres shorten, and short telomeres trigger cell senescence and apoptosis at a threshold of telomere length, thereby limiting cell proliferative lifespan. While telomerase is consistently repressed during cell differentiation to mature somatic cells in man, telomerase is active in a number of somatic tissues in mice. However, little is known as to how telomerase activity is regulated in vivo under physiological conditions.
The complete study
http://www.nature.com/cr/journal/v18/n11/full/cr2008291a.html
