Role of Lkb1 , the causative gene of Peutz–Jegher's syndrome, in embryogenesis and polyposis

Abstract

Peutz-Jeghers syndrome (PJS) is a dominantly inherited human disorder characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. LKB1 (STK11) serine͞threonine kinase is the product of the causative gene of PJS, which has been mapped to chromosome 19p13.3. However, several studies have produced results that are not consistent with a link between LKB1 gene mutation and PJS. We constructed a knockout gene mutation of Lkb1 to determine whether it is the causative gene of PJS and to examine the biological role of the Lkb1 gene. Lkb1 ؊/؊ mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, Lkb1 ؊/؊ embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10-to 14-month-old Lkb1 ؉/؊ mice. Our results indicate that functional Lkb1 is required for normal embryogenesis and that it is related to tumor development. The Lkb1 ؉/؊ mouse is suitable for studying molecular mechanism underlying the development of inherited gastric tumors in PJS.tumor ͉ embryo development

A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma

“…Homozygous deletion of STK11/LKB1 in mice leads to embryonic lethality at midgestation (E11.0), indicating that STK11/LKB1 plays an important role in embryogenesis (Ylikorkala et al, 2001;Jishage et al, 2002). Interestingly, most of the STK11/LKB1 þ /À mice developed intestinal polyps by the age of 45 weeks, identical to those observed in patients with PJS (Bardeesy et al, 2002;Jishage et al, 2002;Nakau et al, 2002). These results suggested that haploinsufficiency in the STK11/ LKB1 þ /À animals is sufficient to induce polyposis as in humans (Su et al, 1999;Rossi et al, 2002).…”

“…The Stk11/Lkb1 protein is ubiquitously expressed in all human fetal and adult tissues (Rowan et al, 2000). Homozygous deletion of STK11/LKB1 in mice leads to embryonic lethality at midgestation (E11.0), indicating that STK11/LKB1 plays an important role in embryogenesis (Ylikorkala et al, 2001;Jishage et al, 2002). Interestingly, most of the STK11/LKB1 þ /À mice developed intestinal polyps by the age of 45 weeks, identical to those observed in patients with PJS (Bardeesy et al, 2002;Jishage et al, 2002;Nakau et al, 2002).…”

LKB1; linking cell structure and tumor suppression

“…Heterozygous mice are viable but develop hamartomatous polyps, characteristic of PJS, with high penetrance (Bardeesy et al, 2002;Jishage et al, 2002;Miyoshi et al, 2002;Rossi et al, 2002).…”

“…Jansen et al (2006) provide a complete discussion on this point as well as an explanation for the occasional findings of carcinomatous changes within haramartomatous polyps. Furthermore, hamartomas display variable LOH of LKB1 as opposed to carcinomas in PJS patients where LOH is more frequently observed (Wang et al, 1999;Miyaki et al, 2000;Entius et al, 2001;Bardeesy et al, 2002;Jishage et al, 2002;Miyoshi et al, 2002;Rossi et al, 2002;De Leng et al, 2003). Most intriguingly, studies in genetically engineered mouse models have called into question whether the hamartomas arise because of cell autonomous processes (a cell autonomous process involves only genotypically mutant cells exhibiting a mutant phenotype; a non-cell autonomous process involves a genotypically mutant cell causing a mutant phenotype in another cell).…”

“…Lkb1 +/À Bardeesy et al, 2002;Jishage et al, 2002;Miyoshi et al, 2002;Rossi et al, 2002 [SM22-CreERT2;Lkb1 .…”