Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro‐differentiative gene PC3

Abstract

Medulloblastoma, the most common brain tumor in childhood, appears to originate from cerebellar granule cell precursors (GCPs), located in the external granular layer (EGL) of the cerebellum. The antiproliferative gene PC3 (Tis21/BTG2) promotes cerebellar neurogenesis by inducing GCPs to shift from proliferation to differentiation. To assess whether PC3 can prevent the neoplastic transformation of GCPs and medulloblastoma development, we crossed transgenic mice conditionally expressing PC3 (TgPC3) in GCPs with Patched1 heterozygous mice (Ptc(+/-)), a model of medulloblastoma pathogenesis characterized by hyperactivation of the Sonic Hedgehog pathway. Perinatal up-regulation of PC3 in Ptc(+/-)/TgPC3 mice results in a decrease of medulloblastoma incidence of approximately 40% and in a marked reduction of preneoplastic abnormalities, such as hyperplastic EGL areas and lesions. Moreover, overexpression of cyclin D1, hyperproliferation, and defective differentiation--observed in Ptc(+/-) GCPs--are restored to normality in Ptc(+/-)/TgPC3 mice. The PC3-mediated inhibition of cyclin D1 expression correlates with recruitment of PC3 to the cyclin D1 promoter, which is accompanied by histone deacetylation. Remarkably, down-regulation of PC3 is observed in preneoplastic lesions, as well as in human and murine medulloblastomas. As a whole, this indicates that PC3 may prevent medulloblastoma development by controlling cell cycle and promoting differentiation of GCPs.

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

“…This is consistent with the repression of BTG2 expression in several human tumors including the breast, thymus, prostate and kidney (Lim et al, 1995;Ficazzola et al, 2001;Kawakubo et al, 2004Kawakubo et al, , 2006Struckmann et al, 2004). Moreover, expression of BTG2 in a mouse model for medulloblastoma suppressed the formation of tumors (Farioli-Vecchioli et al, 2007). Although BTG2 has been shown to interact with transcription factors (Prevot et al, 2000), promote mRNA deadenylation and turnover (Mauxion et al, 2008(Mauxion et al, , 2009) and modulate signaling through its interaction with signaling molecules (Park et al, 2004;Hong et al, 2005), the precise mechanism by which its loss contributes to tumor progression is not well understood.…”

Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma

“…7F), as evidenced by the recapitulation and repression of MB cell phenotypes by Nkx2-2as deficiency and overexpression, respectively. These observations are in accordance with previous reports that BTG2 plays an essential role in counteracting the development of Shh-type MB (34,40). Similarly, crosstalk between the Hippo pathway and Shh signaling has been documented in the pathogenesis of MB (35,41).…”

Nurr1 Protein Is Required for N-Methyl-d-aspartic Acid (NMDA) Receptor-mediated Neuronal Survival

“…Accordingly, we detected upregulation of the ␣1, ␥2, and ␦ subunits of the GABA A receptor and a reduction of the catalytic subunit of calcineurin, postulated to be responsible for the maturation blockade of CGCs (44). 6 Several genes, related to the development and/or survival of CGCs, were also up-regulated in NMDA-treated cells, such as Bdnf, neurocalcin, Vgf, and Pcsk1/3 (31,(45)(46)(47)(48)(49). We decided to cross-check the list of genes that were up-regulated in NMDA-treated CGCs at 3 h with the list of up-regulated genes obtained by Zhang et al (30) after an action potential-bursting condition.…”