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Added to Mdm2. HIPK2 is a protein that regulates Mdm2 in this way.

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HIPK2, Cyclin-dependent kinase 9

While there is some information on function and interactions for these genes/proteins, the information is very limited. Both pages have infoboxes, which are useful to have.I plan to compile information on the gene of choice in the previously unaddressed categories of discovery, homology, structure, localization, regulation, mutation, and related diseases.

Article Evaluation

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I have chosen to evaluate the article Cyclin-dependent kinase 9.

The article is written in the neutral tone, that is appropriate for wikipedia. Several interactions are listed and referenced. There is a decent amount of content in the function section, however the article requires more detail and the creation of more sections to provide the context in which these functions are taking place. Localization, Structure, and Regulation sections could greatly improve the understanding of how the enzyme functions. The lead section is very minimal and should increase in size once there is a full article to summarize. The liks work and the sources are reliable. The information is concise and does not distract from the main concept.

Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.[1] HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors.[2] It belongs to a family of protein kinases known as the DYRK kinases.[3] Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3.[4] HIPK2 can be found in a wide variety of species and interacts with several different proteins. Its functions in gene expression and apoptosis are regulated by several different mechanisms. Abhorrent function and regulation of HIPK2 is associated with human disease.

Discovery

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HIPK2 was discovered concurrently with HIPKs 1 and 3 in 1998. The HIPKs were discovered during an experiment that tried to identify genes that when expressed yielded products that interacted with transcription factors related to the NK homeodomain .[4] They were discovered using a technique called Two-hybrid screening, in conjunction with cDNA cloning, in which embryonic mouse cDNA libraries were used with mouse homeoprotein Nkx-1.2 to find genes involved with homeodomain transcription factors.[4] The researchers found two clones that were similar in protein sequence, demonstrated a strong interaction with the homeoprotein, and an active site characteristic of protein kinases.[4] These characteristics led to the name "HIPK". In 2000, the location of the HIPK2 gene was discovered to be on the long arm of Chromosome 7 (human) in the human genome.[3] In mice HIPK2 was discovered to be on Chromosome 6.[3]

Homology

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There is evidence to suggest that HIPKs including HIPK2 are evolutionarily conserved proteins across a wide array of species. The human sequence shares a close similarity to a sequence from the genome of Caenorhabditis elegans.[4] HIPKs also share a close similarity with YAK1 in yeast and are in the same family as a kinase fromDictyostelium.[3][4] Furthermore, HIPKs are able to interact with homeoproteins from other species, such as NK-1 and NK-3 in Drosophila as well as Nkx-2.5 in mice.[4] HIPK2 can also be found in dogs[5], cats[6], sheep[7], and zebrafish[8] as well as many other species.

Localization

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Expression in tissues

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HIPK2 is expressed in nearly all tissue types, however it is highly expressed in the heart, muscle and kidneys[9] HIPK2 has been shown to be expressed at the highest levels in the brain and neuronal tissues.[10] In addition to adult tissues, HIPK2 is also expressed late in the development of the Human embryo, specifically in the retina, muscles, and neural tissues.[10]

Sub-Cellular Localization

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HIPK2 is found in the nucleus within structures called nuclear speckles.[3][11] It is also associated with PML bodies, which are also structures found in the nucleus.[12] Despite being found predominately in the nucleus, HIPK2 can also be Cytoplasmic.[13]

Gene Structure/ Protein Structure

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Gene

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The HIPK2 gene contains 13 exons and 13 introns within the entire 59.1 Kilo-base pair sequence.[14][15] Along with the other HIPKs, it contains three conserved sequences. A protein kinase domain, an interaction domain, a PEST sequence, and a YH domain.[4] Alternative splicing produces three different messenger RNAs, which subsequently lead to the production of three Protein isoforms.[16]

Protein

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The HIPK2 protein is 1198 amino acids in length and has a molecular weight of 130.97 kilodaltons.[17][18]The most abundant amino acids in the protein are serine, threonine and alanine, which make up approximately 30 percent of the proteins total amino acid count.[17] The structure of the protein in its native form is unstable.[17] The protein is made up of several regions which directly relate to its function, regulation, and localization. The protein kinase domain is 330 amino acids long and is located near the N-terminus of the protein.[19][20] In addition to its kinase domain, HIPK2 has two nuclear localization signals[21], a SUMO interaction motif[21], an auto-inhibitory domain[22], a transcriptional co-repression domain[9], and several interaction domains, including one for p53.[23] While there are signals targeting HIPK2 to nuclear speckles, there is also a speckle retention sequence that causes HIPK2 to remain in the nuclear speckles.[24] The auto-inhibitory domain, which contains an ubiquitylation site at the K1182 residue is located at the C-terminus.[25]

Biological Function

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HIPK2 has two major functions. It acts as a co-repressor for NK homeodomain transcription factors, increasing their DNA binding affinity and their repressive effect on transcription.[4] HIPK2 participates in the regulation of gene expression through its contribution to regulating homeobox genes.These genes encode transcription factors that act to regulate target genes.[4] HIPK2 also acts in signal transduction, specifically the pathway leading to programmed cell death (apoptosis). HIPK2 can promote apoptosis either in association with p53 or by a separate mechanism. HIPK2 phosphorylates the S46 residue of p53, leading to its activation, which in turn leads to the transcription of factors that induce apoptosis.[26] Phosphorylation of p53 by HIPK2 prevents the association of negative regulator Mdm2 to p53 and is neccesary for the acetylation of the K382 residue in p53, which also serves as a functionally important modification.[26] HIPK2 indirectly enhances p53 activity by phosphorylating negative regulators of p53, such as CtBP land Mdm2, leading to their degradation by the proteasome.[26][27] HIPK2 also has the ability to regulate cellular response to reactive oxygen species by regulating the expression of both oxidant and antioxidant genes.[28]

Regulation

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HIPK2 is regulated by other proteins, as well as cellular conditions and post-translational modifications.[29][28][30][31]

Positive

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Under conditions of DNA damage, HIPK2 is stabilized and subject to positive regulation.The activity of HIPK2 is increased through the action of caspase 6.[24] Caspase 6 cleaves HIPK2 at residue D916 and D977.[24] As a result, the auto-inhibitory domain is removed and the activity of HIPK2 increases. HIPK2 activity can also be increased through the action of checkpoint kinases. These kinases phosphorylate HIPK2 associated ubiquitin ligases and prevent their binding to HIPK2. As a result, the degradation of HIPK2 through the ubiquitin proteasome pathway is inhibited.[24][29] In conditions of oxidative stress, sumoylation of HIPK2 prevents acetylation, and as a result maintains its function in facilitating apoptosis.[28] Under normal physiological conditions however, acetylation of HIPK2 by a protein called P300 again stabilizes HIPK2 but , increases its ability to induce apoptosis.[30] Phosphorylation of HIPK2 at residues T880 and S882, via another kinase or through auto-phosphorylation, leads to the recruitment of PIN1 and stabilization of HIPK2.[31] This results in increased apoptotic function of HIPK2.[31]

Negative

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Under regular conditions HIPK2 is unstable and is subject to negative regulation. HIPK2 is subject to regulation by the ubiquitin proteasome pathway, in which ubiquitin ligases bind to HIPK2, leading to polyubiquitination at the K1182 residue, localization to the proteasome and subsequent degradation of the protein. leads to protein degradation.[24][32] The PEST sequence found in HIPK2 is also linked to protein degradation.[33]HIPK2 activity can also be down regulated by the protein HMGA1, which transports it back to the cytoplasm.[24] In conditions of oxidative stress sumoylation of HIPK2 is discouraged and acetylation is promoted, resulting in its stabilization and the inhibition of its ability to facilitate apoptosis.[28]

p53

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p53 regulates HIPK2 using both positive and negative mechanisms.[24]

Mutations

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Two mutations have been discovered in the speckle retention sequence, both of which are missense.[34] One of which was named R868W, meaning that at residue 868 where the wild type amino acid sequence would have contained an arginine residue, it now contains a tryptophan residue. The other mutation was named N958I, meaning that at residue 958 where the wild type amino acid sequence would have contained an asparagine residue, it now contains an isoleucine residue. The R868W mutation is the result of cytosine to thymine point mutation and the N985I mutation resulted from an adenine to thymine point mutation.[34] The R868W mutation was found in exon 12 and the N985I mutation was found in exon 13.[34] These mutations lead to forms of HIPK2 that are less active and show abhorrent localization to nuclear speckles.[34] The speckle retention sequence is necessary for HIPK2 function in transcription activation as deletion of this sequence inhibits the function.[34]

Interactions

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HIPK2 interacts with several other proteins:

Implications on Human Health

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Improper HIPK2 function has been implicated in the pathology of diseases such as acute myeloid leukemia[34], myelodysplastic syndrome[34] through mutations in the speckle retention sequence and Alzheimer's disease through hyperdegradation of HIPK2[35].Consistent with its tissue expression patterns, loss of HIPK2 function has also been implicated in kidney fibrosis[36] and cardiovascular disease.[37]

References 

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  1. ^ Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin K, Hug H (Mar 2001). "Isolation and characterization of cDNAs for the protein kinase HIPK2". Biochimica et Biophysica Acta. 1518 (1–2): 168–72. doi:10.1016/S0167-4781(00)00308-0. PMID 11267674.
  2. ^ Sung, Ki Sa; Go, Yoon Young; Ahn, Jin-Hyun; Kim, Young Ho; Kim, Yongsok; Choi, Cheol Yong (2005-06-06). "Differential interactions of the homeodomain-interacting protein kinase 2 (HIPK2) by phosphorylation-dependent sumoylation". FEBS letters. 579 (14): 3001–3008. doi:10.1016/j.febslet.2005.04.053. ISSN 0014-5793. PMID 15896780.
  3. ^ a b c d e Hofmann, Thomas G; Mincheva, Antoaneta; Lichter, Peter; Dröge, Wulf; Lienhard Schmitz, M (2000-12-01). "Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34". Biochimie. 82 (12): 1123–1127. doi:10.1016/S0300-9084(00)01196-2.
  4. ^ a b c d e f g h i j Kim, Y. H.; Choi, C. Y.; Lee, S. J.; Conti, M. A.; Kim, Y. (1998-10-02). "Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors". The Journal of Biological Chemistry. 273 (40): 25875–25879. ISSN 0021-9258. PMID 9748262.
  5. ^ "HIPK2 homeodomain interacting protein kinase 2 [Canis lupus familiaris (dog)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  6. ^ "HIPK2 homeodomain interacting protein kinase 2 [Felis catus (domestic cat)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  7. ^ "HIPK2 homeodomain interacting protein kinase 2 [Ovis aries (sheep)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  8. ^ "hipk2 homeodomain interacting protein kinase 2 [Danio rerio (zebrafish)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  9. ^ a b Pierantoni, Giovanna Maria; Bulfone, Alessandro; Pentimalli, Francesca; Fedele, Monica; Iuliano, Rodolfo; Santoro, Massimo; Chiariotti, Lorenzo; Ballabio, Andrea; Fusco, Alfredo (2002-01-25). "The Homeodomain-Interacting Protein Kinase 2 Gene Is Expressed Late in Embryogenesis and Preferentially in Retina, Muscle, and Neural Tissues". Biochemical and Biophysical Research Communications. 290 (3): 942–947. doi:10.1006/bbrc.2001.6310.
  10. ^ a b Wang, Ying; Hofmann, Thomas G; Runkel, Laura; Haaf, Thomas; Schaller, Heinz; Debatin, Klaus-Michael; Hug, Hubert (2001-03-19). "Isolation and characterization of cDNAs for the protein kinase HIPK21The nucleotide sequence data have been deposited in GenBank under the accession numbers AF208291 and AF208292, respectively.1". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1518 (1): 168–172. doi:10.1016/S0167-4781(00)00308-0.
  11. ^ Kim, Young Ho; Choi, Cheol Yong; Kim, Yongsok (1999-10-26). "Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12350–12355. ISSN 0027-8424. PMID 10535925.
  12. ^ Sung, Ki Sa; Lee, Yun-Ah; Kim, Eui Tae; Lee, Seung-Rock; Ahn, Jin-Hyun; Choi, Cheol Yong (2011-04-15). "Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear bodies and regulation of p53". Experimental Cell Research. 317 (7): 1060–1070. doi:10.1016/j.yexcr.2010.12.016. ISSN 1090-2422. PMID 21192925.
  13. ^ Sombroek, D; Hofmann, T G (2008-10-31). "How cells switch HIPK2 on and off". Cell Death and Differentiation. 16 (2): 187–194. doi:10.1038/cdd.2008.154. ISSN 1476-5403.
  14. ^ mieg@ncbi.nlm.nih.gov, Danielle Thierry-Mieg and Jean Thierry-Mieg, NCBI/NLM/NIH,. "AceView: Gene:HIPK2, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2017-11-28.{{cite web}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  15. ^ Zhang, Diya; Li, Ke; Erickson-Miller, Connie L.; Weiss, Mitch; Wojchowski, Don M. (2005-01-01). "DYRK gene structure and erythroid-restricted features of DYRK3 gene expression". Genomics. 85 (1): 117–130. doi:10.1016/j.ygeno.2004.08.021.
  16. ^ "HIPK2 - Homeodomain-interacting protein kinase 2 - Homo sapiens (Human) - HIPK2 gene & protein". www.uniprot.org. Retrieved 2017-11-28.
  17. ^ a b c "ExPASy - ProtParam". web.expasy.org. Retrieved 2017-11-28.
  18. ^ He, Qin; Shi, Jingxue; Sun, Hong; An, Jie; Huang, Ying; Sheikh, M. Saeed (2010). "Characterization of Human Homeodomain-interacting Protein Kinase 4 (HIPK4) as a Unique Member of the HIPK Family". Molecular and cellular pharmacology. 2 (2): 61–68. ISSN 1938-1247. PMC 2876313. PMID 20508833.{{cite journal}}: CS1 maint: PMC format (link)
  19. ^ Feng, Yuanyuan; Zhou, Lihong; Sun, Xiaoting; Li, Qi (2017-01-18). "Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies". Oncotarget. 8 (12): 20452–20461. doi:10.18632/oncotarget.14723. ISSN 1949-2553. PMC 5386776. PMID 28107201.{{cite journal}}: CS1 maint: PMC format (link)
  20. ^ Kuwano, Yuki; Nishida, Kensei; Akaike, Yoko; Kurokawa, Ken; Nishikawa, Tatsuya; Masuda, Kiyoshi; Rokutan, Kazuhito (2016-09-27). "Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome". International Journal of Molecular Sciences. 17 (10). doi:10.3390/ijms17101638. ISSN 1422-0067. PMC 5085671. PMID 27689990.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  21. ^ a b de la Vega, Laureano; Fröbius, Katrin; Moreno, Rita; Calzado, Marco A.; Geng, Hui; Schmitz, M. Lienhard (February 2011). "Control of nuclear HIPK2 localization and function by a SUMO interaction motif". Biochimica Et Biophysica Acta. 1813 (2): 283–297. doi:10.1016/j.bbamcr.2010.11.022. ISSN 0006-3002. PMID 21145359.
  22. ^ Feng, Yuanyuan; Zhou, Lihong; Sun, Xiaoting; Li, Qi (2017-01-18). "Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies". Oncotarget. 8 (12): 20452–20461. doi:10.18632/oncotarget.14723. ISSN 1949-2553. PMC 5386776. PMID 28107201.{{cite journal}}: CS1 maint: PMC format (link)
  23. ^ Kim, Eun-Joo; Park, Jong-Sup; Um, Soo-Jong (2002-08-30). "Identification and characterization of HIPK2 interacting with p73 and modulating functions of the p53 family in vivo". The Journal of Biological Chemistry. 277 (35): 32020–32028. doi:10.1074/jbc.M200153200. ISSN 0021-9258. PMID 11925430.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ a b c d e f g Sombroek, D; Hofmann, T G (2008-10-31). "How cells switch HIPK2 on and off". Cell Death and Differentiation. 16 (2): 187–194. doi:10.1038/cdd.2008.154. ISSN 1476-5403.
  25. ^ Kuwano, Yuki; Nishida, Kensei; Akaike, Yoko; Kurokawa, Ken; Nishikawa, Tatsuya; Masuda, Kiyoshi; Rokutan, Kazuhito (October 2016). "Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome". International Journal of Molecular Sciences. 17 (10). doi:10.3390/ijms17101638.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ a b c Puca, R.; Nardinocchi, L.; Givol, D.; D'Orazi, G. (2010-08-05). "Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells". Oncogene. 29 (31): 4378–4387. doi:10.1038/onc.2010.183. ISSN 1476-5594. PMID 20514025.
  27. ^ Zhang, Qinghong; Yoshimatsu, Yasuhiro; Hildebrand, Jeffrey; Frisch, Steven M.; Goodman, Richard H. (2003-10-17). "Homeodomain Interacting Protein Kinase 2 Promotes Apoptosis by Downregulating the Transcriptional Corepressor CtBP". Cell. 115 (2): 177–186. doi:10.1016/S0092-8674(03)00802-X. ISSN 0092-8674. PMID 14567915.
  28. ^ a b c d de la Vega, Laureano; Grishina, Inna; Moreno, Rita; Krüger, Marcus; Braun, Thomas; Schmitz, M. Lienhard (2012-05-25). "A Redox-Regulated SUMO/Acetylation Switch of HIPK2 Controls the Survival Threshold to Oxidative Stress". Molecular Cell. 46 (4): 472–483. doi:10.1016/j.molcel.2012.03.003. {{cite journal}}: no-break space character in |last= at position 3 (help)
  29. ^ a b Winter, Melanie; Sombroek, Dirk; Dauth, Ilka; Moehlenbrink, Jutta; Scheuermann, Karin; Crone, Johanna; Hofmann, Thomas G. (2008-06-08). "Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR". Nature Cell Biology. 10 (7): 812–824. doi:10.1038/ncb1743. ISSN 1476-4679.
  30. ^ a b Choi, Jong-Ryoul; Lee, Seo-Young; Shin, Ki Soon; Choi, Cheol Yong; Kang, Shin Jung (November 23, 2017). "p300-mediated acetylation increased the protein stability of HIPK2 and enhanced its tumor suppressor function". Scientific Reports. 7 (1). doi:10.1038/s41598-017-16489-w. ISSN 2045-2322.
  31. ^ a b c Wook Choi, Dong; Yong Choi, Cheol (2014-10-29). "HIPK2 modification code for cell death and survival". Molecular & Cellular Oncology. 1 (2). doi:10.1080/23723548.2014.955999. ISSN 2372-3548. PMC 4905192. PMID 27308327.{{cite journal}}: CS1 maint: PMC format (link)
  32. ^ Winter, Melanie; Sombroek, Dirk; Dauth, Ilka; Moehlenbrink, Jutta; Scheuermann, Karin; Crone, Johanna; Hofmann, Thomas G. (2008-06-08). "Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR". Nature Cell Biology. 10 (7): 812–824. doi:10.1038/ncb1743. ISSN 1476-4679.
  33. ^ Rinaldo, Cinzia; Prodosmo, Andrea; Mancini, Francesca; Iacovelli, Stefano; Sacchi, Ada; Moretti, Fabiola; Soddu, Silvia (2007-03-09). "MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis". Molecular Cell. 25 (5): 739–750. doi:10.1016/j.molcel.2007.02.008. ISSN 1097-2765. PMID 17349959.
  34. ^ a b c d e f g Li, X.-L.; Arai, Y.; Harada, H.; Shima, Y.; Yoshida, H.; Rokudai, S.; Aikawa, Y.; Kimura, A.; Kitabayashi, I. (2007-11-08). "Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription". Oncogene. 26 (51): 7231–7239. doi:10.1038/sj.onc.1210523. ISSN 0950-9232. PMID 17533375.
  35. ^ Lanni, Cristina; Nardinocchi, Lavinia; Puca, Rosa; Stanga, Serena; Uberti, Daniela; Memo, Maurizio; Govoni, Stefano; D'Orazi, Gabriella; Racchi, Marco (2010). "Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival". PLoS ONE. 5 (4). doi:10.1371/journal.pone.0010171.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  36. ^ Fan, Ying; Wang, Niansong; Chuang, Peter; He, John C. (November 2014). "Role of HIPK2 in kidney fibrosis". Kidney International Supplements. 4 (1): 97–101. doi:10.1038/kisup.2014.18. ISSN 2157-1724. PMC 4536960. PMID 26312158.{{cite journal}}: CS1 maint: PMC format (link)
  37. ^ Guo, Yuanjun; Sui, Jennifer; Zhang, Qinkun; Barnett, Joey; Force, Thomas; Lal, Hind (2017-11-14). "Abstract 18728: Loss of Homeodomain-Interacting Protein Kinase 2 in Cardiomyocytes Leads to Cardiac Dysfunction". Circulation. 136 (Suppl 1): A18728–A18728. ISSN 0009-7322.
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