Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73

Abstract

Down-regulation of the Kpm/Lats2 tumor suppressor is observed in various malignancies and associated with poor prognosis in acute lymphoblastic leukemia. We documented that Kpm/Lats2 was markedly decreased in several leukemias that were highly resistant to conventional chemotherapy. Silencing of Kpm/Lats2 expression in leukemic cells did not change the rate of cell growth but rendered the cells more resistant to DNA damageinducing agents. Expression of p21 and IntroductionThe Warts (Wts) tumor suppressor gene (also termed Lats after large tumor suppressor) was first identified by mitotic recombination of somatic cells and screening for homozygous mutants with overproliferation phenotype in Drosophila melanogaster. 1,2 This discovery initiated a series of genetic studies in Drosophila that led to the delineation of a new signaling network named the Hippo pathway, which is now known to regulate cell growth, cell survival, and organ size in developing animals. [3][4][5] This pathway consists of a kinase cascade in its core where Hippo (Hpo) phosphorylates and activates Wts/Lats, 6 which then in turn phosphorylates and inactivates Yorkie (Yki), a transcription coactivator. Inactivation of Yki results in control of cell survival and cell growth through downregulation of Drosophila inhibitor of apoptosis 1 (Diap1) and Cyclin E. 7 Salvador (Sav), 8,9 a scaffold protein for Hpo, and Mats (mob as tumor suppressor), 10-12 a partner and potentiater of Wts, are also essential components of this pathway. Furthermore, recent evidence has placed Expanded (EX), Merlin (Mer), 13 both 4.1 family proteins, and Fat (FT), 14-17 the atypical cadherin, in the upstream of the Hippo pathway although their connection to the kinase cascade is largely based on genetic epitasis. The Hippo pathway is believed to be conserved throughout species because some of the mammalian homologues have been shown to compensate the corresponding defects in the Drosophila Hippo pathway. At present, however, only a small part of the mammalian Hippo pathway has been experimentally substantiated.Kpm (alternatively named Lats2) is one of the 2 human homologues of Drosophila Wts. 18,19 In parallel to Drosophila Wts, we and others have shown the critical involvement of Kpm/Lats2 in regulation of cell growth and survival. Kpm/Lats2 overexpression results in the cell cycle arrest in G2/M phase via inhibition of Cdc2-Cyclin B kinase activity leading eventually to apoptosis, 20 inhibition of G1/S transition via down-regulation of Cyclin E/Cdk2 kinase activity, 21 or apoptosis via down-regulation of Bcl-2 and Bcl-xL. 22 Kpm/Lats2 binds to Mdm2 and inhibits its E3 ubiquitin ligase activity, resulting in the stabilization of p53 and leading to the p53-dependent G1/S arrest in nocodazole-treated cells. 23 Moreover, Kpm/Lats2 is a target gene of p53 both in mammalian as well as in Drosophila cells, 24,25 suggesting that Kpm/Lats2 may be a positive-feedback-loop regulator of p53. Kpm/Lats2 knockout mice are embryonically lethal and fibroblasts isolated from these mice app...

LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

“…In our previous study, we also reported YAP amplification in a subset of MM cells (28). Regarding LATS2, downregulation of LATS2 was reported to be correlated with poor prognosis of leukemia (42) and missense mutation was also reported in lung cancer (43). However, null status of LATS2 such as by homozygous deletion or nonsense mutation was not reported in these malignancies.…”

LATS tumor suppressor: A new governor of cellular homeostasis

“…Firstly, loss of LATS2 was associated with resistance to two chemotherapeutic drugs, doxorubicin or etoposide, in leukemogenic cells. 69 And secondly, simultaneous loss of both LATS1 and LATS2 renders HeLa cells more resistant to the microtubule-damaging drug Taxol. 72 These studies allude to the potential predictive value of LATS in determining treatment outcomes.…”

“…Firstly, in acute lymphoblastic leukemia, it was shown that expression of LATS2 was the most important prognostic factor in predicting both disease-free survival and overall survival when surveying potential prognostic factors. 3 In addition, loss of LATS2 leads to decreased sensitivity to two commonly used chemotherapeutic drugs, doxorubicin and etoposide, in leukemic cell lines, 69 suggesting that expression of LATS2 might also serve as a valuable predictive factor.…”

Hippo signaling pathway and organ size control

“…12 The biological effect of Hpo signaling is likely to be context dependent, and there is evidence that Yap can promote cell death by binding to a p53 family member, p73. 77,78 In Drosophila, Hpo pathway components also play roles in other developmental processes including retina cell patterning, 79 dendrite morphogenesis, 80,81 regulation of oocyte polarity [82][83][84] and salivary gland degeneration. 85 Furthermore, Hpo signaling regulates salivary gland cell death in a PI3K-dependent, but Yki-independent, manner.…”