Hipk2 cooperates with p53 to suppress γ-ray radiation-induced mouse thymic lymphoma

Abstract

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/− and p53−/− mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30% of radiation-induced tumors from both p53+/− and p53−/− mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene.

The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression

“…Several other kinases, including DYRK2, AMP-activated protein kinase (AMPK), p38, and protein kinase C (PKC)-d, also promote S46 phosphorylation (Perfettini et al 2005;Yoshida et al 2006;Taira et al 2007;Okoshi et al 2008). Mice with heterozygous loss of HIPK2 and p53 develop more lymphomas after irradiation, suggesting that HIPK2 functionally cooperates with p53 (Mao et al 2012). However, lymphomas developed in p53-null mice still undergo HIPK2 deletion, indicating that HIPK2 also has p53-independent mechanisms of tumor suppression.…”

Identification of Hipk2 as an essential regulator of white fat development

“…Despite this plethora of pathways linked to Hipk2, the known consequences of Hipk2 deletion in the mouse germ line are relatively modest (3)(4)(5), including an expansion of trigeminal sensory neurons (4) and altered maturation of dopaminergic neurons (5). Hipk2 has also been implicated in cancer development, either as a suppressor of skin tumors and lymphoma or as an oncogene amplified in pilocytic astrocytomas, but the mechanisms that underlie these phenotypes are not known (1,2,(6)(7)(8).…”

Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

“…There is growing evidence that HIPK2 acts as a tumor suppressor both in mice and men (7)(8)(9)(10) and that the kinase is functionally deregulated by cellular and candidate viral oncogenes (11). In addition to its role in cancer, HIPK2 dysregulation has been linked to pathophysiology including neurodegeneration and kidney fibrosis (7,12,13).…”