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. 2008 Nov 1;112(9):3856-66.
doi: 10.1182/blood-2007-09-111773. Epub 2008 Jun 18.

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

Masahiro Kawahara  1 , Toshiyuki Hori, Kazuhisa Chonabayashi, Tsutomu Oka, Marius Sudol, Takashi Uchiyama
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Free article

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

Masahiro Kawahara et al. Blood. .
Free article

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 damage-inducing agents. Expression of p21 and PUMA was strongly induced by these agents in control cells, despite defective p53, but was only slightly induced in Kpm/Lats2-knockdown cells. DNA damage-induced nuclear accumulation of p73 was clearly observed in control cells but hardly detected in Kpm/Lats2-knockdown cells. Chromatin immunoprecipitation (ChIP) assay showed that p73 was recruited to the PUMA gene promoter in control cells but not in Kpm/Lats2-knockdown cells after DNA damage. The analyses with transient coexpression of Kpm/Lats2, YAP2, and p73 showed that Kpm/Lats2 contributed the stability of YAP2 and p73, which was dependent on the kinase function of Kpm/Lats2 and YAP2 phosphorylation at serine 127. Our results suggest that Kpm/Lats2 is involved in the fate of p73 through the phosphorylation of YAP2 by Kpm/Lats2 and the induction of p73 target genes that underlie chemosensitivity of leukemic cells.

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