Hip-1

protein
Name=huntingtin interacting protein 1
caption=


width=
HGNCid=4913
Symbol=HIP1
AltSymbols=
EntrezGene=3092
OMIM=601767
RefSeq=NM_005338
UniProt=O00291
PDB=
ECnumber=
Chromosome=7
Arm=q
Band=11.23
LocusSupplementaryData=

Huntingtin Interacting Protein or Hip-1 for short is a protein that interacts with the huntingtin protein. It is known to contain a domain homologous to the death effector domains (DED) found on proteins involved in apoptosis. It is believed that accumulation of high levels of the free form of this protein (free as in dissociated from the huntingtin and free to bind other key protein(s)) in the cell is one of the mechanisms by which neuron cell death is caused in Huntington's Disease (via the caspase-3 route).

Huntingtin interacting protein 1 (HIP1) was first identified by Wanker et al in 1997 [Wanker, E. E., C. Rovira, et al. (1997). " HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system." Hum Mol Genet 6: 487–495.] . HIP1 was found to bind to Htt in an N-terminal dependent manner, and co-localise with Htt in the CNS although the nature of this interaction with respect to muHtt was not identified. It has since been found that the CAG expansion seen with muHtt results in decreased binding affinity for HIP1, thus causing disruption of HIP1’s usual function, and also an increased in free HIP1 [Hackam, A. S., A. S. Yassa, et al. (2000). "Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain." J Biol Chem 275(52): 41299-308.] . It is likely that this decreased affinity plays a role in mediating HD pathogenesis, due to loss of cytoskeletal integrity and induction of apoptosis. HIP1’s pro apoptotic effect may involve activation of caspase-8 and a novel HIP1 protein interactor HIPPI [Gervais, F. G., R. Singaraja, et al. (2002). "Recruitment and activation of caspase-8 by the Huntingtin-interacting protein HIP-1 and a novel partner Hippi." Nat. Cell. Biol. 4(2): 95-105.] . HIP1’s non-pathological activity includes clathrin assembly via interaction with clathrin light chains [Legendre-Guillemin, V., M. Metzler, et al. (2003). "HIP1 (huntingtin interacting protein1) regulates clathrin assembly through direct binding to the regulatory region of the clathrin light chain. ." J Biol Chem 280(7): 6101-6110.] . HIP1 is the human homologue of Sla2p, a membrane protein in the periphery [Holzmann, C., T. Schmidt, et al. (2001). "Functional characterization of the human Huntington's disease gene promoter." Brain Res Mol Brain Res 92(1-2): 85-97.] . Sla2p is an actin-binding protein involved in endocytosis, thus indicating HIP1 in this role.

HIP1 has also been found to be overexpressed in some cancers including a subset of colorectal and prostate cancers [Rao, D. S., T. S. Hyun, et al. (2002). "Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival." J Clin Invest 110(3): 351-60.] . This is of specific interest because prostate cancer disease progression involves altered transcription/expression of the androgen receptor (AR) [Chen, C. D., D. S. Welsbie, et al. (2004). "Molecular determinants of resistance to antiandrogen therapy." Nat Med 10(1): 33-9.] . The AR is a nuclear hormone receptor transcription factor that contains polyglutamine repeats. In 2005 Mills and colleagues showed that HIP1 is able to regulate transcription of hormone receptors via the androgen response element (ARE) and also alters the rate of degradation of the AR [Mills, I. G., L. Gaughan, et al. (2005). "Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors." J Cell Biol 170(2): 191-200.] . It is likely that HIP1 is also able to regulate, or at least interact with proteins that also possess the ARE.

References