Promyelocytic leukemia protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1.
Promyelocytic leukemia protein (PML) was originally identified as part of a chromosomal translocation that contributes to the development of acute promyelocytic leukemia (APL). Since its discovery, PML has been found to play diverse roles in different cellular processes. Notably, PML has anti-proliferative and pro-apoptotic activity that supports its role as a tumor suppressor. We have previously shown that the peptidyl-prolyl isomerase Pin1 is able to affect cell proliferation and hydrogen peroxide (H(2)O(2))-mediated cell death through modulation of the steady-state levels of PML. We have extended these studies to show that the interaction between PML and Pin1 is targeted by multiple extracellular signals in the cell. We show that H(2)O(2) up-regulates and IGF-1 down-regulates PML expression in a Pin1-dependent manner. Interestingly, we found that H(2)O(2)- and IGF-1-mediated alteration in PML accumulation regulate MDA-MB-231 cell migration. Furthermore, we show that the control of cell migration by PML, and thus H(2)O(2) and IGF-1, results from PML-dependent decreased expression of integrin beta1 (ITGB1). Knockdown of Pin1 leads to decreased cell migration, lower levels of ITGB1 expression and resistance to IGF-1- and H(2)O(2)-induced changes in cell migration and ITGB1 expression. Taken together, our work identifies PML as a common target for H(2)O(2) and IGF-1 and supports a novel tumor suppressive role for PML in controlling cell migration through the expression of ITGB1.
Reineke
Erin L
EL
Department of Biochemistry, School of Medicine, Case Western Reserve University, the Case Comprehensive Cancer Center, and University Hospitals of Cleveland, Cleveland, Ohio 44106.
Liu
Yu
Y
Department of Biochemistry, School of Medicine, Case Western Reserve University, the Case Comprehensive Cancer Center, and University Hospitals of Cleveland, Cleveland, Ohio 44106.
Kao
Hung-Ying
HY
Department of Biochemistry, School of Medicine, Case Western Reserve University, the Case Comprehensive Cancer Center, and University Hospitals of Cleveland, Cleveland, Ohio 44106. Electronic address: hxk43@cwru.edu.
D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D008856:Microscopy, Fluorescence / Q000379:methods; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014945:Wound Healing
D019012:Integrin beta1; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase