Biomedical subjects

H N Pemberton

Publications and source records attributed to H N Pemberton.

3 recordsLinked to original sources

PubMed2006

Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity.

Genetic instability (GI) is a hallmark feature of tumor development. Securin, also known as pituitary tumor transforming gene (PTTG), is a mitotic checkpoint protein which is highly expressed in numerous cancers, is associated with tumor invasiveness, and induces GI in thyroid cells. We used fluorescence inter-simple sequence repeat PCR to assess GI caused primarily by DNA breakage events in 19 colorectal tumors. GI values ranged significantly, with Dukes' stage C&D colorectal tumors exhibiting greater GI and higher securin expression than Dukes' stage A&B tumors. Consistent with these findings, we observed a dose-dependent increase in GI in HCT116 cells in response to securin overexpression, as well as in non-transformed human fibroblasts. As securin has been implicated in a novel DNA repair pathway in fission yeast, we investigated its potential role in chemotoxic DNA damage response pathways in mammalian cells, using host cell reactivation assays. Securin overexpression in HCT116 cells inhibited etoposide-induced double-stranded DNA damage repair activity, and repressed Ku heterodimer function. Additionally, we observed that securin and Ku70 showed a reciprocal cytosol-nuclear translocation in response to etoposide-induced dsDNA damage. Our data suggest that, by repressing Ku70 activity and inhibiting the non-homologous end-joining dsDNA repair pathway, securin may be a critical gene in the development of GI in colorectal cancer.

Animals↗

PubMed2006

Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction.

Thyroid hormones (THs) are essential for normal fetal development, with even mild perturbation in maternal thyroid status in early pregnancy being associated with neurodevelopmental delay in children. Transplacental transfer of maternal THs is critical, with increasing evidence suggesting a role for 3,3',5-tri-iodothyronine (T3) in development and function of the placenta itself, as well as in development of the central nervous and other organ systems. Intrauterine growth restriction (IUGR) is associated with fetal hypothyroxinaemia, a factor that may contribute to neurodevelopmental delay. The recent description of monocarboxylate transporter 8 (MCT8) as a powerful and specific TH membrane transporter, and the association of MCT8 mutations with profound neurodevelopmental delay, led us to explore MCT8 expression in placenta. We describe the expression of MCT8 in normal human placenta throughout gestation, and in normal third-trimester placenta compared with that associated with IUGR using quantitative reverse transcriptase PCR. MCT8 mRNA was detected in placenta from early first trimester, with a significant increase with advancing gestation (P=0.007). In the early third trimester, MCT8 mRNA was increased in IUGR placenta compared with normal samples matched for gestational age (P<0.05), but there was no difference between IUGR and normal placenta in the late third trimester. Western immunoblotting findings in IUGR and normal placentae were in accord with mRNA data. MCT8 immunostaining was demonstrated in villous cytotrophoblast and syncytiotrophoblast as well as extravillous trophoblast cells from the first trimester onwards with increasingly widespread immunoreactivity seen with advancing gestation. In conclusion, expression of MCT8 in placenta from early gestation is compatible with an important role in TH transport during fetal development and a specific role in placental development. Altered expression in placenta associated with IUGR may reflect a compensatory mechanism attempting to increase T3 uptake by trophoblast cells.

Adult↗

PubMed2005

Thyroid hormones and fetal brain development.

Thyroid hormones are intricately involved in the developing fetal brain. The fetal central nervous system is sensitive to the maternal thyroid status. Critical amounts of maternal T3 and T4 must be transported across the placenta to the fetus to ensure the correct development of the brain throughout ontogeny. Severe mental retardation of the child can occur due to compromised iodine intake or thyroid disease. This has been reported in areas of the world with iodine insufficiency, New Guinea, and also in mother with thyroid complications such as hypothyroxinaemia and hyperthyroidism. The molecular control of thyroid hormones by deiodinases for the activation of thyroid hormones is critical to ensure the correct amount of active thyroid hormones are temporally supplied to the fetus. These hormones provide timing signals for the induction of programmes for differentiation and maturation at specific stages of development. Understanding these molecular mechanisms further will have profound implications in the clinical management of individuals affected by abnormal maternal of fetal thyroid status.

Animals↗