Kif3a is necessary for initiation and maintenance of medulloblastoma.

Abstract:

:Medulloblastoma (MB) cells arise from granule neuron precursors (GNPs) that have lost growth control. During normal development, GNPs divide in response to Sonic hedgehog (SHH), a ligand that binds to the patched (PTCH) receptor on GNPs. If one copy of the Ptch gene is lost, as in human Gorlin's syndrome and in Ptch(+/-) mice, MBs may form. Proper transduction of the SHH signal critically depends on primary cilia. Loss of primary cilia results in improper signal reception and failure to properly activate SHH target genes. KIF3a, part of a kinesin motor, is required for formation of primary cilia. Here, we use tamoxifen-induced ablation of Kif3a in GNPs of postnatal Ptch(+/-) mouse cerebella to show that KIF3a is necessary for MB formation. To investigate the importance of primary cilia in established tumors, we deleted Kif3a from cultured cells and from tumor cell grafts. The loss of Kif3a from established tumors led to their growth arrest and regression. MBs behave as if they are addicted to the presence of primary cilia. These results underscore the potential utility of agents that disrupt cilia for the treatment of Hh pathway-related MBs.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Barakat MT,Humke EW,Scott MP

doi

10.1093/carcin/bgt041

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

1382-92

issue

6

eissn

0143-3334

issn

1460-2180

pii

bgt041

journal_volume

34

pub_type

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