the nucleus within structures called nuclear speckles. It is also associated with PML bodies, which are also structures found in the nucleus. Despite being found predominately in the nucleus, HIPK2 can also be Cytoplasmic. Structure Gene The HIPK2 gene contains 13 exons and 13 introns within the entire 59.1 Kilo-base pair sequence. Along with the other HIPKs, it contains three conserved sequences: a protein kinase domain, an interaction domain, a PEST sequence, and a YH domain. Alternative splicing produces three different messenger RNAs, which subsequently lead to the production of three Protein isoforms. Protein The HIPK2 protein is 1198 amino acids in length and has a molecular weight of 130.97 kilodaltons. 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. The structure of the protein in its native form is unstable. 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. In addition to its kinase domain, HIPK2 has two nuclear localization signals, a SUMO interaction motif, an auto-inhibitory domain a transcriptional co-repression domain, and several interaction domains, including one for p53. 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. The auto-inhibitory domain, which contains an ubiquitylation site at the K1182 residue is located at the C-terminus. Function 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. 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. 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. Phosphorylation of p53 by HIPK2 prevents the association of negative regulator Mdm2 to p53 and is necessary for the acetylation of the K382 residue in p53, which also serves as a functionally important modification. Proper folding of p53 is