Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on a 10-year-old boy with a normal karyotype and a chromosome 13q14 deletion of the retinoblastoma gene (RB1) by fluorescence in situ hybridization (FISH). He showed subtle signs of overgrowth, including macrocephaly, hepatomegaly, and inguinal hernia. The boy also had cryptorchism and mild developmental delay. In his first months of life, variant Wiedemann-Beckwith syndrome was tentatively suspected and he was included in a careful tumor prevention program. At the age of 11 months, bifocal retinoblastoma of the left eye was diagnosed. Pinealoma was suspected at the age of 19 months and was removed by neurosurgery at the age of 29 months. At 4 years and 4 months, the deletion of the RB1 gene was suspected on clinical grounds and was diagnosed by FISH and molecular studies. At that time, he was a near-normal healthy playful kindergarten child, height 107 cm (-0.3 SD), OFC 52.5 cm (+0.8 SD), developmental age 3-3.5 years. The combination of retinoblastoma, pinealoma, and deletion of the RB1 gene diagnosed by FISH has not been reported previously. The deletion spans at least 370-420 kb in size and is predicted to include proximal and distal neighbor genes. This report may assist in establishing the clinical signs of the contiguous gene syndrome at the RB1 locus on 13q14.
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PMID:Retinoblastoma, pinealoma, and mild overgrowth in a boy with a deletion of RB1 and neighbor genes on chromosome 13q14. 1473 89

Diverse etiologic events are associated with the development of hepatocellular carcinoma. During hepatocarcinogenesis, genetic events likely occur that subsequently cooperate with long-term exposures to further drive the progression of hepatocellular carcinoma. In this study, the frequent loss of the retinoblastoma (RB) tumor suppressor in hepatocellular carcinoma was modeled in response to diverse hepatic stresses. Loss of RB did not significantly affect the response to a steatotic stress as driven by a methionine- and choline-deficient diet. In addition, RB status did not significantly influence the response to peroxisome proliferators that can drive hepatomegaly and tumor development in rodents. However, RB loss exhibited a highly significant effect on the response to the xenobiotic1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene. Loss of RB yielded a unique proliferative response to this agent, which was distinct from both regenerative stresses and genotoxic carcinogens. Long-term exposure to 1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene yielded profound tumor development in RB-deficient livers that was principally absent in RB-sufficient tissue. These data demonstrate the context specificity of RB and the key role RB plays in the suppression of hepatocellular carcinoma driven by xenobiotic stress.
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PMID:RB tumor suppressive function in response to xenobiotic hepatocarcinogens. 2472 45

Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP-treatment in mice and potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and hepatocyte proliferation using hepatocyte-specific Yap-KO mice. AAV8-TBG-CRE vector was injected to Yap-floxed mice for achieving hepatocyte-specific Yap deletion followed by TCPOBOP-treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and Ugt1a1). However, Yap deletion substantially reduced TCPOBOP-induced hepatocyte proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes mainly related to proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these proliferation genes via alerting expression of Myc and Foxm1, two critical transcriptional regulators of CAR-mediated hepatocyte proliferation. Conclusion: Our study revealed an important role of Yap signaling in CAR-driven hepatocyte proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.
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PMID:Yap is crucial for CAR-driven hepatocyte proliferation, but not for induction of drug metabolism genes in mice. 3279 2