TY - JOUR
T1 - Rac-GAP-dependent inhibition of breast cancer cell proliferation by β2-chimerin
AU - Yang, Chengfeng
AU - Liu, Ying
AU - Leskow, Federico Coluccio
AU - Weaver, Valerie M.
AU - Kazanietz, Marcelo G.
PY - 2005/7/1
Y1 - 2005/7/1
N2 - β2-Chimerin is a member of the "non-protein kinase C" intracellular receptors for the second messenger diacylglycerol and the phorbol esters that is yet poorly characterized, particularly in the context of signaling pathways involved in proliferation and cancer progression. β2-Chimerin possesses a C-terminal Rac-GAP (GTPase-activating protein) domain that accelerates the hydrolysis of GTP from the Rac GTPase, leading to its inactivation. We found that β2-chimerin messenger levels are significantly down-regulated in human breast cancer cell lines as well as in breast tumors. Adenoviral delivery of β2-chimerin into MCF-7 breast cancer cells leads to inhibition of proliferation and G1 cell cycle arrest. Mechanistic studies show that the effect involves the reduction in Rac-GTP levels, cyclin D1 expression, and retinoblastoma dephosphorylation. Studies using the mutated forms of β2-chimerin revealed that these effects were entirely dependent on its C-terminal GAP domain and Rac-GAP activity. Moreover, MCF-7 cells stably expressing active Rac (V12Rac1) but not RhoA (V14RhoA) were insensitive to β2-chimerin-induced inhibition of proliferation and cell cycle progression. The modulation of G1/S progression by β2-chimerin not only implies an essential role for Rac in breast cancer cell proliferation but also raises the intriguing possibility that diacylglycerol-regulated non-protein kinase C pathways can negatively impact proliferation mechanisms controlled by Rho GTPases.
AB - β2-Chimerin is a member of the "non-protein kinase C" intracellular receptors for the second messenger diacylglycerol and the phorbol esters that is yet poorly characterized, particularly in the context of signaling pathways involved in proliferation and cancer progression. β2-Chimerin possesses a C-terminal Rac-GAP (GTPase-activating protein) domain that accelerates the hydrolysis of GTP from the Rac GTPase, leading to its inactivation. We found that β2-chimerin messenger levels are significantly down-regulated in human breast cancer cell lines as well as in breast tumors. Adenoviral delivery of β2-chimerin into MCF-7 breast cancer cells leads to inhibition of proliferation and G1 cell cycle arrest. Mechanistic studies show that the effect involves the reduction in Rac-GTP levels, cyclin D1 expression, and retinoblastoma dephosphorylation. Studies using the mutated forms of β2-chimerin revealed that these effects were entirely dependent on its C-terminal GAP domain and Rac-GAP activity. Moreover, MCF-7 cells stably expressing active Rac (V12Rac1) but not RhoA (V14RhoA) were insensitive to β2-chimerin-induced inhibition of proliferation and cell cycle progression. The modulation of G1/S progression by β2-chimerin not only implies an essential role for Rac in breast cancer cell proliferation but also raises the intriguing possibility that diacylglycerol-regulated non-protein kinase C pathways can negatively impact proliferation mechanisms controlled by Rho GTPases.
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U2 - 10.1074/jbc.M411629200
DO - 10.1074/jbc.M411629200
M3 - Article
C2 - 15863513
AN - SCOPUS:21644476814
SN - 0021-9258
VL - 280
SP - 24363
EP - 24370
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -