PBXIP1 regulates erythroid differentiation by activating the PI3K (see 171833)/AKT (164730) pathway (Manavathi et al., 2012).

Abramovich et al. (2000) cloned human PBXIP1, which they called HPIP, from a human bone marrow CD34 (142230)-positive cDNA library. The predicted 731-amino acid HPIP protein has a calculated molecular mass of 80 kD and contains a coil-coil domain, 2 putative nuclear localization signals, and a leucine-rich region. RT-PCR analysis showed that HPIP was coexpressed with PBX1 (176310) in the CD34-positive compartment of primitive human hematopoietic cells. Northern blot analysis detected HPIP transcripts in erythroid K562 and myeloid HL60 cells. Fluorescence-tagged HPIP was expressed mainly in the cytosol of transfected NIH-3T3 and RAT1 cells, with a small amount in the nucleus. HPIP had an apparent molecular mass of 98 kD by SDS-PAGE, suggesting posttranslational modifications or SDS-resistant folding.

By RT-PCR analysis, Manavathi et al. (2012) showed that Hpip was expressed in mouse hematopoietic tissues, such as spleen, bone marrow, and thymus. Hpip expression was also detected in purified mouse common myeloid progenitors and common granulocyte and macrophage progenitors.

Gross (2020) mapped the PBXIP1 gene to chromosome 1q21.3 based on an alignment of the PBXIP1 sequence (GenBank BC016852) with the genomic sequence (GRCh38).

Using yeast 2-hybrid analysis and in vitro and in vivo binding assays, Abramovich et al. (2000) showed that human HPIP interacted with PBX1. The interaction required the homeodomain of PBX1 and its immediate N-terminal flanking sequence. HPIP interaction blocked formation of heterodimeric DNA-binding complexes between PBX1 and HOXB proteins, including HOXB7 (142962). HPIP also inhibited the transcriptional activation capacity of the E2A (TCF3; 147141)-PBX1 complex.

Wang et al. (2008) found that human HPIP interacted with both ER-alpha (ESR1; 133430) and ER-beta (ESR2; 601663) in mammalian cells. Overexpression and knockdown analyses revealed that HPIP interaction increased expression of ER-alpha target genes by enhancing phosphorylation of ER-alpha at ser167 by MAPK (see 176948) and AKT. Immunoprecipitation experiments demonstrated that ER-beta also interacted with ER-alpha, thereby decreasing binding of ER-alpha to HPIP and inhibiting expression of ER-alpha target genes.

Using overexpression and knockdown analyses, Manavathi et al. (2012) showed that HPIP expression promoted erythroid differentiation of human CD34-positive cells. Similarly, HPIP expression positively regulated erythroid differentiation of K562 cells through activation of the PI3K/AKT pathway. HPIP gene transcription was activated by E/Meg transcription factors, especially GATA1 (305371) and CEBPA (116897). GATA1 and CEBPA were recruited to the HPIP promoter in response to cell differentiation signals and activated HPIP transcription in K562 cells. The HPIP promoter region also contained a binding site for CTCF (604167), a chromatin insulator. CTCF and GATA1 regulated HPIP transcription in K562 cells by forming an active transcription complex in a DNA methylation-sensitive manner.