Citations

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27 Kip1 and p18 Ink4c . Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27 Kip1 and p18 Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27 Kip1 and p18 Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.

Background and Purpose— Internal carotid artery (ICA) occlusion is an important cause of transient ischemic attack (TIA) and cerebral infarction. There are no previous population-based natural history studies evaluating outcome after symptomatic ICA occlusion (SICAO). Methods— We performed a retrospective, population-based study of SICAO. All Olmsted County (Minnesota) residents with possible SICAO from 1986 to 2000 were identified by cross-referencing appropriate clinical and imaging codes. Inclusion criteria were cerebral infarction or TIA in a carotid distribution and imaging documentation of ipsilateral ICA occlusion <3 months after the index event. Kaplan–Meier estimates were used to calculate the risk of cerebral infarction, myocardial infarction, and death after SICAO. Results— Seventy-five patients qualified. Annual SICAO incidence was 6 per 100 000 persons (age and gender adjusted to the 2000 US white population). Risk of cerebral infarction during follow-up was 8% at 30 days, 10% at 1 year, and 14% at 5 years. Five of 11 cerebral infarctions occurred within the first week after diagnosis of occlusion. Risk of myocardial infarction was 0% at 30 days, 8% at 1 year, and 24% at 5 years. Risk of death was 7%, 13%, and 29%, respectively. Conclusions— There may be 15 000 to 20 000 incident cases of SICAO in the United States annually. Risk of cerebral infarction after SICAO is initially high and then stabilizes, whereas risk of myocardial infarction is initially low but gradually increases. Better strategies are needed to reduce early stroke recurrence in this setting.

The function of Type 1, classic cadherins depends on their association with the actin cytoskeleton, a connection mediated by α- and β-catenin. The phosphorylation state of β-catenin is crucial for its association with cadherin and thus the association of cadherin with the cytoskeleton. We now show that the phosphorylation of β-catenin is regulated by the combined activities of the tyrosine kinase Fer and the tyrosine phosphatase PTP1B. Fer phosphorylates PTP1B at tyrosine 152, regulating its binding to cadherin and the continuous dephosphorylation of β-catenin at tyrosine 654. Fer interacts with cadherin indirectly, through p120ctn. We have mapped the interaction domains of Fer and p120ctn and peptides corresponding to these sequences release Fer from p120ctn in vitro and in live cells, resulting in loss of cadherin-associated PTP1B, an increase in the pool of tyrosine phosphorylated β-catenin and loss of cadherin adhesion function. The effect of the peptides is lost when a β-catenin mutant with a substitution at tyrosine 654 is introduced into cells. Thus, Fer phosphorylates PTP1B at tyrosine 152 enabling it to bind to the cytoplasmic domain of cadherin, where it maintains β-catenin in a dephosphorylated state. Cultured fibroblasts from mouse embryos targeted with a kinase-inactivating ferD743R mutation have lost cadherin-associated PTP1B and β-catenin, as well as localization of cadherin and β-catenin in areas of cell-cell contacts. Expression of wild-type Fer or culture in epidermal growth factor restores the cadherin complex and localization at cell-cell contacts.