View source for Huntingtin-interacting protein 1

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Huntingtin-interacting protein 1''' also known as HIP-1 is a [[protein]] that in humans is encoded by the HIP1 gene.

Hip-1 is a protein that interacts with the [[huntingtin]] protein. It is known to contain a [[protein domain|domain]] homologous to the [[death effector domain]]s (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).  The role of Hip-1 in caspase mediated cell death remains unclear.

== Discovery ==

Huntingtin interacting protein 1 (HIP1) was first identified by Wanker et al. in 1997.<ref>{{cite journal | vauthors = Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Wälter S, Tait D, Colicelli J, Lehrach H | title = HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system | journal = Human Molecular Genetics | volume = 6 | issue = 3 | pages = 487–95 | date = Mar 1997 | pmid = 9147654 | doi=10.1093/hmg/6.3.487| doi-access = free }}</ref>

== Function ==
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 {{notatypo|muHtt}} was not identified.  It has since been found that the CAG expansion seen with {{notatypo|muHtt}} results in decreased binding affinity for HIP1, thus causing disruption of HIP1’s usual function, and also an increase in free HIP1.<ref>{{cite journal | vauthors = Hackam AS, Yassa AS, Singaraja R, Metzler M, Gutekunst CA, Gan L, Warby S, Wellington CL, Vaillancourt J, Chen N, Gervais FG, Raymond L, Nicholson DW, Hayden MR | title = Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain | journal = The Journal of Biological Chemistry | volume = 275 | issue = 52 | pages = 41299–308 | date = Dec 2000 | pmid = 11007801 | doi = 10.1074/jbc.M008408200 | doi-access = free }}</ref>  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.<ref>{{cite journal | vauthors = Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, Hackam AS, Tam J, Vaillancourt JP, Houtzager V, Rasper DM, Roy S, Hayden MR, Nicholson DW | title = Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi | journal = Nature Cell Biology | volume = 4 | issue = 2 | pages = 95–105 | date = Feb 2002 | pmid = 11788820 | doi = 10.1038/ncb735 | s2cid = 10439592 }}</ref>  HIP1’s non-pathological activity includes clathrin assembly via interaction with clathrin light chains.<ref>{{cite journal | vauthors = Legendre-Guillemin V, Metzler M, Lemaire JF, Philie J, Gan L, Hayden MR, McPherson PS | title = Huntingtin interacting protein 1 (HIP1) regulates clathrin assembly through direct binding to the regulatory region of the clathrin light chain | journal = The Journal of Biological Chemistry | volume = 280 | issue = 7 | pages = 6101–8 | date = Feb 2005 | pmid = 15533941 | doi = 10.1074/jbc.M408430200 | doi-access = free }}</ref>  HIP1 is the human homologue of Sla2p, a membrane protein in the periphery.<ref>{{cite journal | vauthors = Holzmann C, Schmidt T, Thiel G, Epplen JT, Riess O | title = Functional characterization of the human Huntington's disease gene promoter | journal = Brain Research. Molecular Brain Research | volume = 92 | issue = 1–2 | pages = 85–97 | date = Aug 2001 | pmid = 11483245 | doi=10.1016/s0169-328x(01)00149-8}}</ref>  Sla2p is an actin-binding protein involved in endocytosis, thus indicating HIP1 in this role.  Further details suggesting an important role for Hip-1 in endocytosis comes from binding studies looking at Hip-1 binding to actin.  Actin binding by Hip-1 is altered depending on whether clathrin is also bound to Hip-1.

== Clinical significance ==

HIP1 has also been found to be overexpressed in some cancers including a subset of colorectal and prostate cancers.<ref>{{cite journal | vauthors = Rao DS, Hyun TS, Kumar PD, Mizukami IF, Rubin MA, Lucas PC, Sanda MG, Ross TS | title = Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival | journal = The Journal of Clinical Investigation | volume = 110 | issue = 3 | pages = 351–60 | date = Aug 2002 | pmid = 12163454 | doi = 10.1172/JCI15529 | pmc=151092}}</ref>  This is of specific interest because prostate cancer disease progression involves altered transcription/expression of the androgen receptor (AR).<ref>{{cite journal | vauthors = Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL | title = Molecular determinants of resistance to antiandrogen therapy | journal = Nature Medicine | volume = 10 | issue = 1 | pages = 33–9 | date = Jan 2004 | pmid = 14702632 | doi = 10.1038/nm972 | s2cid = 1182764 }}</ref>  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.<ref>{{cite journal | vauthors = Mills IG, Gaughan L, Robson C, Ross T, McCracken S, Kelly J, Neal DE | title = Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors | journal = The Journal of Cell Biology | volume = 170 | issue = 2 | pages = 191–200 | date = Jul 2005 | pmid = 16027218 | doi = 10.1083/jcb.200503106 | pmc=2171420}}</ref>  It is likely that HIP1 is also able to regulate, or at least interact with proteins that also possess the ARE.

== References ==
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