Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation.
Medulloblastoma, the most common malignant brain tumor of childhood, is believed to derive from immature granule neuron precursors (GNPs) that normally proliferate in the external granule layer before exiting the cell cycle and migrating to their mature location in the inner granule layer. In this study, we examined the expression of D type cyclins in GNPs during cerebellar development and showed that GNPs in early development expressed only cyclin D1, whereas later GNPs expressed both cyclins D1 and D2. Coinciding with the period of cyclin D1-only expression, Ccnd1(-/-) mice showed reduced proliferation of GNPs and impaired growth of the cerebellum. Interestingly, removal of cyclin D1 was sufficient to drastically reduce the incidence of medulloblastoma in Ptch1(+/-) mice, despite the fact that these tumors showed upregulation of both cyclins D1 and D2. We showed that cyclin D1 has an earlier role in tumorigenesis: in the absence of cyclin D1, the incidence and overall volume of ;preneoplastic' lesions were significantly decreased. We propose a model that links a role of cyclin D1 in normal GNP proliferation with its early role in tumorigenesis.
Pogoriler
Jennifer
J
Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Millen
Kathleen
K
Utset
Manuel
M
Du
Wei
W
D000818:Animals; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000737:chemistry / Q000235:genetics*; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008527:Medulloblastoma / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
C486196:Ccnd2 protein, mouse; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface