The phospholipase C β3 gene located in the MEN1 region shows loss of expression in endocrine tumours

Abstract

Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour suppressor gene in this region. Identification of meiotic cross-overs in MEN1 families has placed the MEN1 locus centromeric of D11S807. An extended deletion mapping was performed in 27 primary parathyroid tumours, and identified D11S427 as the closest centromeric flanking marker. Through physical mapping using newly isolated cDNA clones, we estimated the distance between the flanking markers D11S807 and D11S427 to be less than 900 kb. One of these cDNA clones showed expression of a 4.4 kb message in multiple tissues, including those affected in MEN1, while in five endocrine tumours no transcript was detected. Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction.

A 3-Mb Contig from D11S987 to MLK3, a Gene-Rich Region in 11q13: Figure 1.

“…However, the D11S807 STS isolated from the end of the D11S807 containing cosmid cCLGW39 also maps to J1-11, a short arm containing somatic cell hybrids, as well as to the RRH cell hybrids 3A1, 7C1, 2C2, and 33B1. This result is in disagreement with the previously reported placement by pulsed field gel electrophoresis (PFGE), which suggested that D11S807 is within 900 kb of D11S427 (Weber et al 1994). We place D11S427 within the PYGM segregation group by RRH (D.S.…”

“…This is more than twice what was estimated by PFGE (Janson et al 1991;Tanigami et al 1992;Weber et al 1994). However, the genetic distance between PYGM and GSTP is 5 cM (Smith et al 1995a), whereas RRH mapping suggests that SEA and GSTP are separated by at least 1.6 Mb (James et al 1994).…”

“…MLK3 cosegregates with PYGM; FRA1, D11S913, HNP36, D11S460, PC, ACTN, D11S703, D11S951E, D11S1956E, and WI-12191 with SEA;and D11S987 and D11S807 (Alu-PCR) with GSTP1. Genetic markers (PYGM, D11S913, D11S460, D11S987, and D11S807) used previously in family studies (Nakamura et al 1989;Larsson et al 1992;Thakker et al 1993;Leppert et al 1994;Weber et al 1994;Smith et al 1995b), as well as genes/expressed sequence tags (ESTs) (MLK3, FRA1, PC, ACTN, D11S951E, D11S1956E, WI-12191, HNP36, SEA, and GSTP1) were included to integrate the transcription, genetic, and RRH maps.…”

“…A combination of RRH, genetic linkage, and FISH mapping was used to provide an independent confirmation of the results. The establishment of this contig containing genes and ESTs incorporates a transcription map within the physical map and allows for the resolution of a number of marker order inconsistencies found in the literature (Larsson et al 1992;Weber et al 1994). The average density of one probe per 60 kb along the cloned resource provides an excellent framework map for the initiation of large-scale genome sequencing efforts in this very gene-rich region and the precise mapping of additional ESTs made available by the IMAGE consortium.…”

Calmodulin potentiates Gβγ activation of phospholipase C-β3

“…The mechanisms of regulation of PLCβ3 are incompletely understood despite the enzyme's importance in a variety of cellular processes [10][11][12][13][14]. Aberrancies in expression of PLCβ3 can lead to tumorigenesis [13,15,16], and PLCβ3 knockout mice show changes in μ-opioid response [12] or early embryonic lethality [17].…”