PMC:4135037 / 4019-6638 JSONTXT

{"project":"2_test","denotations":[{"id":"24531709-10919634-79171853","span":{"begin":93,"end":94},"obj":"10919634"},{"id":"24531709-10919634-79171853","span":{"begin":93,"end":94},"obj":"10919634"},{"id":"24531709-15545627-79171853","span":{"begin":93,"end":94},"obj":"15545627"},{"id":"24531709-15545627-79171853","span":{"begin":93,"end":94},"obj":"15545627"},{"id":"24531709-17208431-79171853","span":{"begin":93,"end":94},"obj":"17208431"},{"id":"24531709-17208431-79171853","span":{"begin":93,"end":94},"obj":"17208431"},{"id":"24531709-8646780-79171854","span":{"begin":1413,"end":1414},"obj":"8646780"},{"id":"24531709-8646780-79171854","span":{"begin":1413,"end":1414},"obj":"8646780"},{"id":"24531709-8646781-79171854","span":{"begin":1413,"end":1414},"obj":"8646781"},{"id":"24531709-8646781-79171854","span":{"begin":1413,"end":1414},"obj":"8646781"},{"id":"24531709-8646779-79171854","span":{"begin":1413,"end":1414},"obj":"8646779"},{"id":"24531709-8646779-79171854","span":{"begin":1413,"end":1414},"obj":"8646779"},{"id":"24531709-9744866-79171854","span":{"begin":1413,"end":1414},"obj":"9744866"},{"id":"24531709-9744866-79171854","span":{"begin":1413,"end":1414},"obj":"9744866"},{"id":"24531709-10913196-79171854","span":{"begin":1413,"end":1414},"obj":"10913196"},{"id":"24531709-10913196-79171854","span":{"begin":1413,"end":1414},"obj":"10913196"},{"id":"24531709-15545627-79171855","span":{"begin":1573,"end":1574},"obj":"15545627"},{"id":"24531709-15545627-79171855","span":{"begin":1573,"end":1574},"obj":"15545627"},{"id":"24531709-17208431-79171856","span":{"begin":1576,"end":1577},"obj":"17208431"},{"id":"24531709-17208431-79171856","span":{"begin":1576,"end":1577},"obj":"17208431"},{"id":"24531709-10490638-79171857","span":{"begin":1990,"end":1992},"obj":"10490638"},{"id":"24531709-10490638-79171857","span":{"begin":1990,"end":1992},"obj":"10490638"},{"id":"24531709-10319860-79171857","span":{"begin":1990,"end":1992},"obj":"10319860"},{"id":"24531709-10319860-79171857","span":{"begin":1990,"end":1992},"obj":"10319860"},{"id":"24531709-12609976-79171857","span":{"begin":1990,"end":1992},"obj":"12609976"},{"id":"24531709-12609976-79171857","span":{"begin":1990,"end":1992},"obj":"12609976"},{"id":"24531709-16443763-79171857","span":{"begin":1990,"end":1992},"obj":"16443763"},{"id":"24531709-16443763-79171857","span":{"begin":1990,"end":1992},"obj":"16443763"},{"id":"24531709-15315761-79171858","span":{"begin":2309,"end":2311},"obj":"15315761"},{"id":"24531709-15315761-79171858","span":{"begin":2309,"end":2311},"obj":"15315761"},{"id":"24531709-12923533-79171858","span":{"begin":2309,"end":2311},"obj":"12923533"},{"id":"24531709-12923533-79171858","span":{"begin":2309,"end":2311},"obj":"12923533"}],"text":"Cyclin-dependent kinases (CDKs) form central machinery for eukaryotic cell cycle progression 6-8. While yeast cells express a single CDK catalytic subunit differentially activated by multiple Cyclin regulatory subunits, mammalian cells depend on several CDKs for cell cycle control. During the G1 phase, D-type Cyclins bind and activate CDK4 or CDK6, followed by Cyclin E-mediated activation of CDK2. From early S-phase through G2, Cyclin A becomes a predominant activator of CDK2. CDK4/CDK6 and CDK2 collaborate in phosphorylating retinoblastoma protein (RB) and related pocket binding proteins p107 and p130, which is critical for transactivation of S-phase specific E2F target genes. These G1/S-specific CDKs are negatively regulated by several CDK inhibitors. The INK4-family inhibitors, such as p16, p15, p18, and p19, specifically inhibit CDK4 and CDK6. In contrast, the Cip/Kip-family inhibitors such as p21, p27 and p57 bind promiscuously to various Cyclin-CDK complexes. These CDK inhibitors play not only developmental roles but also tissue-specific tumor-suppressive roles, as demonstrated by the phenotypes of mice with targeted disruption of the CDK inhibitor genes. For instance, both p27-null mice and p18-null mice spontaneously develop pituitary adenomas in the intermediate lobe, and p27; p18-double null mice exhibit MEN1-like tumorigenesis in the endocrine pancreas, pituitary and parathyroid 9-13. Recent studies using mice with targeted disruption of CDK genes have suggested that CDK proteins have substantial redundancies in developmental functions 7, 8. Mice with disruption of Cdk2, Cdk4 or Cdk6 are viable with defects in highly specific tissues, despite almost ubiquitous expression of these proteins. Combined CDK deficiencies result in more severe developmental defects and lethality, suggesting functional redundancies. Importantly, Cdk4-null mice display progressive hypoplasia in pancreatic islets and the anterior pituitary postnatally after several weeks 14-17. The tissue spectrum affected by Cdk4 deficiency is similar to that associated with the MEN1 tumorigenesis. In contrast, Cdk6-null mice and Cdk2-null mice exhibit no developmental or functional defects in the neuroendocrine tissues, while they show some defects in hematopoietic and gonadal tissues, respectively 18-20. Thus, we hypothesized that CDK4 plays a unique essential role in driving proliferation of neuroendocrine cells, and menin may negatively regulate the CDK4 action. To evaluate this hypothesis, we examined the impact of Cdk4- or Cdk2-deficiency upon neuroendocrine tumorigenesis in Men1 heterozygous mice."}