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[10]

In 1997, two loci for PJS were identified. The first was mapped to chromosome 19p13.3, near marker D19S886, by genomic hybridization and linkage analyses.[4] Subsequently, a second locus was described on 19q13.4 in the vicinity of D19S891.[14] The following year, two groups pinpointed the PJS gene on 19p13.3. Hemminki et al. noted truncating germline mutations on chromosome 19 in multiple patients with PJS. The gene, called STK11 (or LKB1), is a serine/threonine kinase with strong homology to the Xenopus serine/threonine kinase XEEK1.[15] Jenne et al. described five separate germline mutations in STK11 in a three-generation Peutz-Jeghers family and concluded STK11 mutations are responsible for the development of

PJS in at least a subset of PJS families.[16] STK11 germline mutations have been described in up to 100% of PJS families in some studies, although in other series, STK11 mutations were absent in 33% to 42% of individuals with clinical manifestations of PJS.[17,18] Boardman et al. analyzed five PJS probands and 23 individuals with sporadic PJS, and found STK11 mutations in only two and four patients, respectively. Thus PJS appears to demonstrate genetic heterogeneity, and it is likely that other loci will be implicated in this disease.[13]

The Function of the STK11 Gene Product and Its Role as a Tumor Suppressor Gene

STK11 contains 10 exons spanning 23 kb and is expressed in all human tissues.[16] It encodes a protein kinase that is likely a tumor suppressor, as loss of the normal STK11 allele has been described in the polyps of PJS patients with germline mutations in the other allele.[15] Peutz-Jeghers syndrome therefore became the first cancer-susceptibility condition described due to inactivation of a protein kinase.

Indeed, Mehenni et al. illustrated that mutant STK11 proteins expressed in COS7 cells demonstrated little or no protein kinase activity when compared with wild-type STK11 and proposed that STKll's ability to phosphoryl-ate other proteins was related to its role as a tumor suppressor.[19] The consequences of the deregulated kinase activity observed in STK11 mutant appear to be on the regulation of both cell proliferation and apoptosis. Tiainen et al. demonstrated that reconstituting cancer cells that carry mutant STK11 with wild-type STK11 resulted in a G1 cell cycle arrest and the suppression of cell proliferation demonstrating the role of STK11 as a tumor suppressor gene.[20] STK11 has been shown to regulate cell cycle progression through the induction of the cyclin-dependent kinase inhibitor p21 by a p53-dependent mechanism.[21] In addition to p53-dependent effects on cell cycle arrest, Karuman et al. illustrated the STK11 protein can physically associate with the p53 protein and probably regulates p53-dependent apoptosis.[22] STK11 normally translocates from cytoplasm to nucleus during apoptosis and is significantly upregulated in pyknotic intestinal cells, whereas polyps from PJS patients have been shown to lack STK11 by immunostaining. Thus deficient apoptosis regulation may be an important factor in the formation of intestinal polyps in PJS patients.[22] Consistent with the importance of cellular localization in the function of wild-type STK11, some mutations in STK11 have been shown to affect the normal subcellular localization of STK11. For example, an SL26 mutation found in a PJS family, which results from a small in-frame deletion, produces a protein that retains its kinase activity but only resides in the nucleus, whereas normal STK11 is found in both cytoplasm and nucleus.[23]

Additionally, as demonstrated by Ylikorkala et al., STK11 likely participates in the vascular - endothelial growth factor (VEGF) pathway. Mice with targeted Stk11 disruption died in midgestation, with evidence of neural tube defects and vascular anomalies. These phenotypes were correlated with noticeably increased levels of VEGF mRNA.[24] Bardeesy et al. generated Lkb1+ mice and observed the formation of Peutz-Jeghers polyps in these mice and also found that cells from these mice showed loss of culture-induced senescence and modulation of factors related to angiogenesis, extracellular matrix remodeling, and cell adhesion.[25] Finally, other groups have found that STK11 binds to and regulates Brgl, a protein responsible for inducing cell cycle arrest. The inability of STK11 mutants to mediate Brgl-dependent growth cessation may correlate with the development of the Peutz-Jeghers syndrome.[26]

Specific STK11 Mutations

Mutations in the STK11 gene typically lead to truncation of the protein product.[27] DNA sequencing of tissues from individuals with Peutz-Jeghers syndrome has led to the elucidation of over 100 mutations. Stenson et al. in the Human Gene Mutation Database have collected and categorized all 108 reported STK11 mutations as of March 5, 2004, as follows: 40 missense/nonsense substitutions, 13 splicing substitutions, 30 small deletions, 10 small insertions, 3 small indels, 8 gross deletions, 1 gross insertion and duplication, and 3 complex rearrange-ments[28] (Table 2).

Table 2 Currently identified mutations in STK11
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