The Peutz-Jegher Gene Product LKB1 Is a Mediator of p53-Dependent Cell Death

Abstract

Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

“…In fact, some microtubule-disrupting agents that induce the LKB1-dependent cell death also activate the JNK pathway to promote apoptosis. 19 Another interesting point of our research is that inhibition of LKB1 results in defective epithelial morphogenesis, which is associated with low JNK activity (Supplementary Figure 4 and 5). Several previous studies already demonstrated the requirement of LKB1 and JNK for epithelial integrity and polarity, both in the mammalian and Drosophila systems.…”

“…Consistent with our results, LKB1 was reported to be highly expressed in apoptotic cells of the small intestine in humans, and PJS polyps that lack the functional LKB1 protein possessed fewer apoptotic cells than in adjacent normal tissues. 19 Collectively, these results strongly suggested that instigation of apoptosis is a critical function of tumor suppressor LKB1.…”

“…19,[41][42][43] Therefore, we questioned whether LKB1-dependent apoptosis requires p53 activity. When a dominant-negative p53 was expressed by the gmrGal4 driver, the ionizing radiation-dependent apoptosiswhich is fully dependent on p53 -was specifically suppressed in the gmr-expressing region (Figure 4c, d), demonstrating that the dominant-negative p53 is sufficient to inhibit endogenous p53 activity.…”

“…17,18 In addition, studies showing the absence of apoptosis in PJS polyps revealed that LKB1 is an inducer of apoptosis in vivo. 19 Another tumor suppressor p53, the first identified in vitro substrate of LKB1, was proposed as a mediator of this apoptosis. 19,20 Finally, LKB1 was shown to be necessary for the polarization of intestinal epithelial cells and Drosophila ovary cells, demonstrating another important function of LKB1 in regulating cell structure.…”

“…19 Another tumor suppressor p53, the first identified in vitro substrate of LKB1, was proposed as a mediator of this apoptosis. 19,20 Finally, LKB1 was shown to be necessary for the polarization of intestinal epithelial cells and Drosophila ovary cells, demonstrating another important function of LKB1 in regulating cell structure. 21,22 Although considerable progress has been made to characterize the in vivo function of LKB1, only a limited amount of information concerning its molecular mechanisms has been found in detail; the major biological pathway responsible for the tumor suppressive function of LKB1 remains to be clarified.…”