Kinesin family member 1B (KIF1B) induces apoptosis in neurons in response to nerve growth factor withdrawal and is deleted in many different types of neuronal tumors.
Deletion of the outermost band of the short arm of chromosome 1 (1p36) is often seen in multiple tumour types, including neural crest-derived tumours, giving rise to the hypothesis that this region harbours one or more tumour suppressor genes. Susan Schlisio, Bill Kaelin and colleagues have identified a candidate gene, the kinesin-encoding KIF1B.
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Previous work from the Kaelin laboratory has shown that apoptosis of neuronal cells induced by limiting the levels of nerve growth factor (NGF) requires the prolyl hydroxylase EGLN3. Having verified this in sympathetic neurons from EglN3-wild-type, -heterozygous and -null mice, and shown that expression of EGLN3 induces apoptosis in a variety of cell lines, the authors screened for short hairpin RNAs (shRNAs) that could prevent EGLN3-induced cell death. One of the protective shRNAs that was identified targeted the splice variant of the kinesin 3 family member KIF1B. Various analyses indicated that KIF1B is downstream of EGLN3. For example, expression of KIF1B is required for EGLN3-induced apoptosis in response to NGF withdrawal, and expression of exogenous KIF1B also induced apoptosis. Regulation of KIF1B by EGLN3 seems to be post-translational, but whether this is through hydroxylation is yet to be determined.
The ability of KIF1B to induce apoptosis and its location at 1p36 are consistent with the idea that KIF1B is a tumour suppressor, but are there data from human tumours to support this? Sequencing the 46 coding exons of this splice variant in 111 neuroblastomas (44 that had 1p loss of heterozygosity), 52 pheochromocytomas and 14 medulloblastomas revealed KIF1B missense variants in three neuroblastomas, two pheochromocytomas and one medulloblastoma. The last was a tumour-specific (sporadic) mutation, whereas the other five were germline inherited mutations. Some of the tumours with these germline mutations lost the remaining wild-type KIF1B allele but others apparently did not. However, expression of these variants in rat sympathetic neurons showed that their capacity to induce apoptosis was impaired compared with neurons expressing wild-type KIF1B, indicating that these mutations are unlikely to be passenger mutations.
When the nervous system develops, more neurons are produced than are required and the excess cells are culled by the apoptosis that is induced as a result of competition for growth factors, including NGF. These data indicate that the partial loss of KIF1B function could protect neuroblasts from developmental apoptosis, possibly leading to neuronal tumours such as pheochromocytoma or neuroblastoma. Further studies are required to determine how, mechanistically, KIF1B induces apoptosis and how often, and through which means, its function is deregulated in cancer.
Nicola McCarthy
References
Schlisio, S. et al. The kinesin KIF1B acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumour suppressor. Genes Dev.22, 884-893 (2008) | Article | PubMed |
splice variant of the kinesin 3 family member KIF1B. Various analyses indicated that KIF1B