Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivating mutations in the protein kinase LKB1 lead to a dominantly inherited cancer in humans termed Peutz-Jeghers syndrome. The role of LKB1 is unclear, and only one target for LKB1 has been identified in vivo [3]. AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a pivotal role in energy homeostasis. AMPK may have a role in protecting the body from metabolic diseases including type 2 diabetes, obesity, and cardiac hypertrophy. We previously reported the identification of three protein kinases (Elm1, Pak1, and Tos3 [9]) that lie upstream of Snf1, the yeast homologue of AMPK. LKB1 shares sequence similarity with Elm1, Pak1, and Tos3, and we demonstrated that LKB1 phosphorylates AMPK on the activation loop threonine (Thr172) within the catalytic subunit and activates AMPK in vitro [9]. Here, we have investigated whether LKB1 corresponds to the major AMPKK activity present in cell extracts. AMPKK purified from rat liver corresponds to LKB1, and blocking LKB1 activity in cells abolishes AMPK activation in response to different stimuli. These results identify a link between two protein kinases, previously thought to lie in unrelated, distinct pathways, that are associated with human diseases.
 ...
PMID:LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. 2462 16

Endometrial cancer is increasingly common in affluent Western countries, largely owing to the growing obesity of those populations. There are two recognized types of endometrial cancer: Type I is more common and is associated with obese postmenopausal women and comprises approximately 80% of all endometrial cancers; Type II describes a woman who is often younger and thinner with a more aggressive histologic type that is nonestrogen dependent, of either serous or clear cell histology, and consists of a more aggressive clinical course and results in poorer prognosis. As the majority of patients with endometrial cancer present with symptoms and have early disease, screening is unlikely to be cost effective or reduce the mortality rate. However, surveillance of high-risk populations is a different proposition. Patients who may benefit from routine surveillance include those with a family history of endometrial cancer, a history of hormone replacement therapy with less than 12-14 days of progestogens, long-term use of tamoxifen, hereditary nonpolyposis colorectal cancer family syndrome, Cowden's syndrome, Peutz-Jeghers syndrome, a history of breast cancer and obesity. Most patients with endometrial cancer are offered surgery as first-line therapy. The standard surgical procedure should be an extrafascial total hysterectomy with bilateral salpingo-oophorectomy. Adnexal removal is also recommended, even if the adnexa appear normal, as they may contain micrometastases. The safety of a laparoscopic approach in the surgical management of uterine cancer has not yet been demonstrated in prospective randomized trials, therefore, the field awaits the Gynaecologic Oncology Group's prospective Lap-2 study. While post-treatment follow-up guidelines vary between institutions and countries, in general, patients at high risk of recurrence are followed closely every 3-4 months for the first year or two, then every 6 months to complete 5 years of follow-up.
 ...
PMID:An overview of uterine cancer and its management. 1637 42

The signalling components upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR key signalling molecules are the small GTPase Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are known to be deregulated in many human cancers. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27, known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by TNF-alpha and Wnt, both of which have been shown to play critical roles in the development of many human neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimer's disease, cardiac hypertrophy, obesity and type 2 diabetes is discussed.
 ...
PMID:The mTOR pathway and its role in human genetic diseases. 1859 80

The mammalian target of rapamycin (mTOR) is part of two distinct complexes, mTORC1, containing raptor and mLST8, and mTORC2, containing rictor, mLST8 and sin1. Although great endeavors have already been made to elucidate the function and regulation of mTOR, the cytoplasmic nuclear distribution of the mTOR complexes is unknown. Upon establishment of the proper experimental conditions, we found mTOR, mLST8, rictor and sin1 to be less abundant in the nucleus than in the cytoplasm of non-transformed, non-immortalized, diploid human primary fibroblasts. Although raptor is also high abundant in the nucleus, the mTOR/raptor complex is predominantly cytoplasmic, whereas the mTOR/rictor complex is abundant in both compartments. Rapamycin negatively regulates the formation of both mTOR complexes, but the molecular mechanism of its effects on mTORC2 remained elusive. We describe that in primary cells short-term treatment with rapamycin triggers dephosphorylation of rictor and sin1 exclusively in the cytoplasm, but does not affect mTORC2 assembly. Prolonged drug treatment leads to complete dephosphorylation and cytoplasmic translocation of nuclear rictor and sin1 accompanied by inhibition of mTORC2 assembly. The distinct cytoplasmic and nuclear upstream and downstream effectors of mTOR are involved in many cancers and human genetic diseases, such as tuberous sclerosis, Peutz-Jeghers syndrome, von Hippel-Lindau disease, neurofibromatosis type 1, polycystic kidney disease, Alzheimer's disease, cardiac hypertrophy, obesity and diabetes. Accordingly, analogs of rapamycin are currently tested in many different clinical trials. Our data allow new insights into the molecular consequences of mTOR dysregulation under pathophysiological conditions and should help to optimize rapamycin treatment of human diseases.
 ...
PMID:Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. 1861 46

Cancer of the small intestine is very uncommon. There are 4 main histological subtypes: adenocarcinomas, carcinoid tumors, lymphoma and sarcoma. The incidence of small intestine cancer has increased over the past several decades with a four-fold increase for carcinoid tumors, less dramatic rises for adenocarcinoma and lymphoma and stable sarcoma rates. Very little is known about its etiology. An increased risk has been noted for individuals with Crohn's disease, celiac disease, adenoma, familial adenomatous polyposis and Peutz-Jeghers syndrome. Several behavioral risk factors including consumption of red or smoked meat, saturated fat, obesity and smoking have been suggested. The prognosis for carcinomas of the small intestine cancer is poor (5 years relative survival < 30%), better for lymphomas and sarcomas, and best for carcinoid tumors. There has been no significant change in long-term survival rates for any of the 4 histological subtypes. Currently, with the possible exceptions of obesity and cigarette smoking, there are no established modifiable risk factors which might provide the foundation for a prevention program aimed at reducing the incidence and mortality of cancers of the small intestine. More research with better quality and sufficient statistical power is needed to get better understanding of the etiology and biology of this cancer. In addition, more studies should be done to assess not only exposures of interest, but also host susceptibility.
 ...
PMID:Epidemiology of cancer of the small intestine. 2146 Nov 67

Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several large-volume centers have initiated such screening protocols, and consensus-based guidelines for screening high-risk groups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.
...
PMID:Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. 2517 Feb 3

Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic, and behavioral abnormalities. We report the first case of an unbalanced de novo reciprocal translocation of chromosomes 15 and 19, 45,XY,-15,der(19)t(15;19)(q12;p13.3), resulting in monosomy for the PWS critical chromosome region. Our patient had several typical features of PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet, and food seeking, but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age. He had seizures noted from 1 to 3 years of age and marked cognitive delay. High-resolution SNP microarray analysis identified an atypical PWS type I deletion in chromosome 15 involving the proximal breakpoint BP1. The deletion extended beyond the GABRB3 gene but was proximal to the usual distal breakpoint (BP3) within the 15q11q13 region, and GABRA5, GABRG3, and OCA2 genes were intact. No deletion of band 19p13.3 was detected; therefore, the patient was not at an increased risk of tumors from the Peutz-Jeghers syndrome associated with a deletion of the STK11 gene.
 ...
PMID:Prader-Willi Syndrome due to an Unbalanced de novo Translocation t(15;19)(q12;p13.3). 2789 6

The most frequent pancreatic cancer is pancreatic adenocarcinoma. It has high and early locally and distant invasiveness; this is the reason why it often shows little sign or symptoms in early stage and poor prognosis after the diagnosis, frequently in advanced stage. Although it is possible to detect this tumor in early stage because of its neoplastic precursor (PanINs). Epidemiological data shows that pancreatic cancer is not very common but obvious it is one of the most neoplastic death-cause in the world. The trend of incidence is quite increasing through years, proportionally to the increase of risk factors. About risk factors, it is not easy to detect in all the cases but it is known the role of some of that: there are hereditary risk factors, such as genetic pattern like HBOC, HNPCC, FAP, PJS, FAMMM, HP and CF and environmental ones (modifiable) such as smoke, alcohol consumption, chronic pancreatitis, obesity and diabetes mellitus. This narrative review aims to analyze the epidemiological data of pancreatic cancer and associated risk factors.
 ...
PMID:Epidemiology and risk factors of pancreatic cancer. 3056 7