Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Menin, the product of the Men1 gene mutated in familial multiple endocrine neoplasia type 1 (MEN1), regulates transcription in differentiated cells. Menin associates with and modulates the histone methyltransferase activity of a nuclear protein complex to activate gene expression. However, menin-dependent histone methyltransferase activity in endocrine cells has not been demonstrated, and the mechanism of endocrine tumor suppression by menin remains unclear. Here, we show that menin-dependent histone methylation maintains the in vivo expression of cyclin-dependent kinase (CDK) inhibitors to prevent pancreatic islet tumors. In vivo expression of CDK inhibitors, including p27 and p18, and other cell cycle regulators is disrupted in mouse islet tumors lacking menin. Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters. Moreover, H3 Lys-4 methylation associated with p27 and p18 is reduced in islet tumors from Men1 mutant mice. Thus, H3 Lys-4 methylation is a crucial function of menin in islet tumor suppression. These studies suggest an epigenetic mechanism of tumor suppression: by promoting histone modifications, menin maintains transcription at multiple loci encoding cell cycle regulators essential for endocrine growth control.
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PMID:Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. 1619 83

Carney-complex is the rarest and most recently described form of multiple endocrine neoplasia syndromes that is unique both from clinical and pathogenetic aspects. Clinical features include spotty skin pigmentation, cutaneous and cardiac myxomas, multiple endocrine abnormalities and schwannomas. The most characteristic endocrine abnormality is primary pigmented nodular adrenal hyperplasia that may result in clinically apparent Cushing's syndrome. Acromegaly, hyperprolactinaemia, tumours of the testis and ovaries have also been described. Approximately fifty percent of Carney-complex cases are familial, with an autosomal dominant inheritance pattern. About 45-65% of Carney-complex cases are related to mutations of the PRKAR1A gene encoding a regulatory subunit of protein kinase A, but other genetic mechanisms seem to be involved, as well. Here, the authors present a brief synopsis of its clinical and pathogenetical features.
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PMID:[Clinical features and pathogenesis of Carney complex, a rare form of multiple endocrine neoplasia syndromes]. 1669 79

Hereditary cases of growth hormone (GH)-secreting tumors have been classified into three clinical entities: the multiple endocrine neoplasia type 1 (MEN1) syndrome, the Carney complex (CNC) and the isolated familial somatotropinomas (IFS). The genomic defects associated with MEN1 are all linked to various mutations of the MEN1 gene, which is located at chromosome 11q13 and codes for menin, a nuclear protein expressed in multiple tissues. Inactivation of the MEN1 gene appears to be only rarely associated with sporadic pituitary tumor development. A CNC-associated gene, the type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PRKAR1A), is located at 17q23-24. A second CNC candidate gene is located at chromosome 2p15-16, with characteristics of inheritance consistent with an oncogene; however, this gene has not been identified yet. PRKAR1A mutations are infrequently associated with sporadic GH-secreting adenomas. A candidate IFS gene is located at 11q13, in proximity to the MEN1 gene, at a locus narrowed down to a 2.21-Mb area, with approximately 50 genes, that does not appear to include the MEN1 gene. Apart from the linkage of IFS to 11q13, a possible linkage to 2p16 has also been raised, although data are still inconclusive. This manuscript reviews genetic aspects of hereditary GH-secreting tumors, data from animal models resulting from the inactivation of the MEN1 and PRKAR1A tumor suppressor genes and available in vitro data regarding possible functions of menin, the product of the MEN1 gene.
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PMID:Growth hormone-secreting tumors: genetic aspects and data from animal models. 1704 80

Carney complex (CNC) is a unique multiple endocrine neoplasia syndrome (MIM 160980) which is characterized by unusual biochemical features (chronic hypersomatotropinemia and paradoxical responses of cortisol production to glucocorticoids) and multi-tissue involvement. The gene coding for the protein kinase A (PKA) type 1alpha regulatory subunit, PRKAR1A, had been mapped to 17q22-24, one of the genetic loci involved in CNC, and allelic analysis using probes from this chromosomal region revealed consistent changes in CNC tumors. Sequencing of the PRKAR1A gene in over 100 kindreds showed a number of mutations; in almost all cases, the sequence change was predicted to lead to a premature stop codon, and mutant mRNAs were subject to nonsense-mediated mRNA decay. In CNC cells, PKA activity assays showed increased stimulation by cAMP. Few mutations that did not lead to a premature stop codon have been described; they are also associated with increased PKA activity. PRKAR1A has been investigated in sporadic endocrine tumors; it does not appear to be mutated in pituitary adenomas, but both thyroid and adrenal neoplasms have been found to harbor somatic mutations of this gene. Animal models of the disease have been developed. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems. This has wide implications for cAMP involvement in endocrine tumorigenesis.
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PMID:Carney complex: pathology and molecular genetics. 1704 82

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18(-/-); Men1(+/-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18(-/-) and Men1(+/-) cells and was further increased in p18(-/-); Men1(+/-) cells. The remaining wild-type Men1 allele was lost in most tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-); Men1(+/-) mice. Combined mutations of p27(-/-) and Men1(+/-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that Men1 may regulate additional factor(s) that interact with p18 and p27 differently.
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PMID:p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. 1714 68

In the presence of double strand breaks, DNA damage checkpoint halts cell cycle progression. However, cells ultimately escape the checkpoint arrest and reenter cell cycle in the presence of irreparable DNA damage. cdc5-ad was identified as a mutant that fails to adapt to the cell cycle arrest induced by DNA damage checkpoint. In budding yeast, Cdc5 protein kinase is a component of both MEN and FEAR pathways that are required for mitotic exit. It remains unclear whether the adaptation defect of cdc5-ad mutant cells is related to the function of Cdc5 in mitotic exit. Here we present evidence indicating that cdc5-ad mutant cells exhibit defects in mitotic exit. cdc5-ad mutant cells are sensitive to high dosage of Amn1, a negative regulator of MEN. It also shows synthetic growth defects with mutants in MEN pathway. Moreover, mutants in FEAR pathway exhibit defects in DNA damage adaptation. Thus, we conclude that the compromised mitotic exit pathway contributes to DNA damage adaptation defects in cdc5-ad mutant cells.
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PMID:Budding yeast DNA damage adaptation mutants exhibit defects in mitotic exit. 1717 70

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice and showed that p18, but not p27, functionally collaborates with Men1 in suppressing lung tumorigenesis. Lung tumors developed in both Men1(+/-) and p18(-/-);Men1(+/-) mice at a high penetrance and contain both neuroendocrine and nonneuroendocrine cells. The remaining wild-type Men1 allele was lost in most lung tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-);Men1(+/-) mice, showing a functional collaboration between p18 and Men1 in lung tumor suppression. Phosphorylation of Rb protein at both CDK2 and CDK4/CDK6 sites were significantly increased in normal bronchial epithelia and tumor cells derived from p18(-/-);Men1(+/-) mice compared to those from single p18(-/-) or Men1(+/-) mice. Lung tumors developed in p18(-/-);Men1(+/-) mice were multifocal, more heterogeneous, and highly invasive compared to those developed in either p18(-/-) or Men1(+/-) mice. Bronchioalveolar stem cells are expanded in normal and tumorigenic lungs of p18(-/-) mice and are further expanded in p18(-/-);Men1(+/-) lung tumors. These results reveal a previously unrecognized function of p18 in lung tumor suppression through collaboration with Men1 to control lung stem cell proliferation.
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PMID:p18Ink4c collaborates with Men1 to constrain lung stem cell expansion and suppress non-small-cell lung cancers. 1740 23

Pituitary tumors are among the most common human neoplasms. Although these common lesions rarely become clinically manifest and they are almost never malignant, they are the cause of significant morbidity in affected patients. The genetic causes of common pituitary tumors remain for the most part unknown; progress has been limited to the elucidation of the molecular etiology of four genetic syndromes predisposing to pituitary neoplasias: McCune-Albright syndrome, multiple endocrine neoplasia type 1, Carney complex and, most recently, familial acromegaly and prolactinomas and other tumors caused by mutations in the GNAS, menin, PRKAR1A, AIP, and p27 (CDKN1B) genes, respectively. Intense molecular studies of sporadic pituitary tumors from patients with negative family histories and no other neoplasms have yielded interesting findings with abnormalities in growth factor expression and cell cycle control dysregulation. To add to the difficulties in understanding pituitary tumorigenesis in man, good murine models of these neoplasms simply do not exist: pituitary tumors are common in rodents, but their histologic origin (mostly from the intermediate lobe), age of presentation (late in murine life) and clinical course make them hardly models of their human counterparts. The present report reviews the clinical and molecular genetics of the cAMP-dependent protein kinase pathway in human pituitary tumors; it also reviews briefly other pathways that have been involved in sporadic pituitary neoplasms. At the end, we attempt a unifying hypothesis for pituitary tumorigenesis, taking into account data that are also discussed elsewhere in this issue.
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PMID:Molecular genetics of the cAMP-dependent protein kinase pathway and of sporadic pituitary tumorigenesis. 1761 52

Pituitary adenomas can occur in a familial context, or they can be isolated cases, sometimes due to a predisposing syndrome. In multiple endocrine neoplasia type 1, they often associate with a mutation of the menin gene, a tumor-suppressing gene. A new germinal mutation predisposing to the development of multiple endocrine neoplasias has recently been identified in MENI-negative subjects on the gene CDKN1B encoding for p27(kip1)protein. Carney Complex syndrome--a rare disease--is in more than 60% of the cases linked to the inactivation mutation of a gene located on 17q22-24 that encodes the regulatory subunit 1 of protein kinase A, PRKARIA. Isolated familial pituitary adenomas represent 1.9 to 3.2% of the population of subjects presenting a pituitary adenoma. Low penetrance non-sense mutations, Q14X, IVS3-IG>A and R304X, in 11q12-11q13 region encoding AIP protein, (Aryl hydrocarbon receptor Interacting Protein), have been described by Vierimaa et al, in Finish patients with pituitary adenoma predispositions.
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PMID:[Familial pituitary adenomas: clinical and genetic aspects]. 1796 54

Familial pituitary adenoma is a rare syndrome which may present either as isolated lesions, or in association with other endocrine tumors, for example in the frame of multiple endocrine neoplasia (MEN-1) or Carney complex (CNC). The most frequently described forms of familial isolated pituitary adenoma (FIPA) are familial somatotropinomas or prolactinomas. Recently, some cases of familial isolated somatotropinoma have been associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The present report shows heterogeneous FIPA with 3 subtypes of tumor in 3 individuals of the same family: somatotropinoma in the proband, giant prolactinoma in a brother, and gonadotroph cell macroadenoma in the father. A prospective survey also suggested the occurrence of a silent microadenoma in the proband's sister. Clinical screening was performed in the 3 affected members, the 4th suspected case, and 9 additional, asymptomatic relatives. They had no clinical evidence of associated endocrine lesion suggesting MEN-1 or CNC. Genetic screening for germline mutation of the MEN-1, the gene encoding the protein kinase A (PKA) type 1 alpha regulatory subunit (R1 alpha) (PRKAR1alpha) and AIP gene was negative in 2 affected members. In conclusion, these data suggest that familial pituitary adenomas can occur with a heterogeneous functional pattern that is distinguished from MEN-1 or CNC. The absence of mutation of the recently described AIP gene suggests the implication of other predisposing gene(s). Collaborative, multicentric studies are needed to further define the location of gene(s) involved in heterogeneous FIPA.
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PMID:Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features. 1799 73


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