Mechanistic Insights into the Role of Hematopoietic PBX Interacting Protein in Cell Cycle Regulation

Abstract

Pre-B cell leukaemia homeobox interacting protein (PBXIP1) also known as Hematopoietic newlinePBX-interacting protein (HPIP), is a protooncogene that is notably elevated in various cancer newlinetypes, playing a crucial part in the initiation and progression of cancer. It involves multifaceted newlinefunctions such as cell migration, proliferation, and differentiation. Despite the mechanistic newlinedetails of HPIP-mediated cell migration and differentiation functions are unveiled partially; newlinehow it controls cell proliferation is largely unknown. We followed both gain-of function and newlineloss-of function and gain of function approaches to unravel the role of HPIP in cell division newlineusing HeLa cells. The study uncovered that HPIP is essential for proper cell proliferation as newlinereduced expression of HPIP expression leads to G2/M arrest and delayed mitosis. Mechanistic newlinestudies additionally revealed that HPIP causes cyclin B1 stabilization by alleviating APC/CCdc20 newlineaction towards cyclin B1 to ensure G2/M transition and timely mitosis to occur. newlineInterestingly, HPIP is proteolyzed via APC/C-Cdc20-facilitated ubiquitination in mitosis. newlineFurther investigation revealed that HPIP is subjected to phosphorylation at serine 43 by CDK1- newlinecyclin B1 complex during mitosis. Loss of phosphorylation of HPIP at serine 43 severely newlinehampered HPIP-mediated cell division due to delayed mitotic entry and exit in HeLa cells. newlineAdditionally, loss of serine 43 phosphorylation in HPIP results in improper chromosomal newlinesegregation and the formation of abnormal spindle poles. Further mechanistic studies revealed newlinethat mtHPIP-S43A failed to stabilize cyclin B1 and timely G2/M transition because loss of newlineHPIP phosphorylation by CDK1-cyclin B1 complex impairs its proteolysis by APC/C-Cdc20. newlineCollectively, these findings indicated an essential role for HPIP and its phosphorylation at newlineserine 43 by CDK1 in cell division. newline