Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modern theory of tumorigenesis suggests that genetic alterations may play a role in the initiation and promotion of pituitary adenomas. Gsp and MEN-1 genes play a role in the initiation event, while p53, ras, Rb and nm23 genes play some role in the progression of the tumor. Gsp gene, that may play an important role in 40% of GH-producing tumor, activation of 10% of non-functioning tumors and 6% of corticotroph adenomas, produces cAMP, which stimulates cyclin D1 and D3 which later produce cdk2 and cdk4 respectively, and stimulates cell progression from G1 to S phase. cAMP also induces ras gene, which inhibits binding of pRb with E2F that is necessary to prevent action of E2F in accelerating cell cycle. MEN-1 gene, although found in some sporadic tumors, is more likely associated with familial adenoma. p53, Ras, Rb, nm23 and c-myc genes play some role in the promotion of tumors especially toward their aggressive variant. p53 gene, which is found in up to 60% of ACTH producing adenomas, through action of p21 inhibits progression of cell cycle from G1 to S phase, by inhibiting the action of cyclin D3 on cdk4. Ras oncogene, in cooperation with c-myc gene, prevents the binding of pRb with E2F, which is necessary for preventing progression cell cycle, resulting in progression of cell cycle from G1 to S phase. Nm23 gene inhibits the action of cyclin B and arrests the cell in G2 phase. Further studies will not only be helpful in understanding the genetic pathogenesis and prognosis of pituitary tumors, but also in developing a novel treatment for patients with pituitary adenomas.
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PMID:Molecular pathogenesis of pituitary adenomas: a review. 1048 84

Cushing disease caused by adrenocorticotropin (ACTH)-secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity, and increased mortality. There is no effective pituitary targeted pharmacotherapy for Cushing disease. Here, we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene (PTTG/securin) targeted to the adenohypophyseal proopiomelanocortin (POMC) lineage, which recapitulated early features pathognomonic of corticotroph adenomas, including corticotroph expansion and partial glucocorticoid resistance. Adult Tg:Pomc-Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up-regulation, as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease. Early development of corticotroph pathologies in Tg:Pomc-Pttg embryos facilitated drug testing in vivo. We identified a pharmacologic CDK2/cyclin E inhibitor, R-roscovitine (seliciclib; CYC202), which specifically reversed corticotroph expansion in live Tg:Pomc-Pttg embryos. We further validated that orally administered R-roscovitine suppresses ACTH and corticosterone levels, and also restrained tumor growth in a mouse model of ACTH-secreting pituitary adenomas. Molecular analyses in vitro and in vivo showed that R-roscovitine suppresses ACTH expression, induces corticotroph tumor cell senescence and cell cycle exit by up-regulating p27, p21 and p57, and downregulates cyclin E expression. The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion.
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PMID:Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. 2153 83

When obesity is caused by consumption of a high-fat diet, the tumor suppressor pRb is phosphoinactivated in the neurons of the mediobasal hypothalamus, a brain area critical for energy-balance regulation. However, the functional relevance of pRb phosphoinactivation in the mediobasal hypothalamus to diet-induced obesity remains unknown. Here, we show that inhibiting pRb phosphorylation in the mediobasal hypothalamus can prevent and treat diet-induced obesity in mice. Expressing an unphosphorylable pRb nonselectively in the mediobasal hypothalamus or conditionally in anorexigenic POMC neurons inhibits diet-induced obesity. Intracerebroventricular delivery of US Food and Drug Administration-approved (FDA-approved) cyclin-dependent kinase 4 (CDK4) inhibitor abemaciclib inhibits pRb phosphorylation in the mediobasal hypothalamus and prevents diet-induced obesity. Oral administration of abemaciclib at doses approved for human use reduces fat mass in diet-induced obese mice by increasing lipid oxidation without significantly reducing lean mass. With analysis of recent literature identifying CDK4 as the most abundantly expressed neuronal CDK in the mediobasal hypothalamus, our work uncovers CDK4 as the major kinase for hypothalamic pRb phosphoinactivation and a highly effective central antiobesity target. As three CDK4/6 inhibitors have recently received FDA approval for life-long breast cancer therapy, our study provides a preclinical basis for their expedient repurposing for obesity management.
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PMID:Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity. 3018 66