Kim Doyil, Akcakanat Argun, Singh Gopal, Sharma Chandeshwar, Meric-Bernstam Funda
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Growth Factors. 2009 Feb;27(1):12-21. doi: 10.1080/08977190802556986.
Ribosomal protein S6 kinase 1 (S6K1), a critical mediator of cell growth, is overexpressed in breast cancer and is associated with poor prognosis. S6K1 has two known isoforms, p85(S6K1) and p70(S6K1). p85(S6K1) is characterized by 23 additional amino acids in the N-terminus of p70(S6K1). This is thought to target p85(S6K1) to the nucleus, while p70(S6K1) is mainly cytoplasmic. We sought to determine the activation, regulation, and function of p70(S6K1) and p85(S6K1) in breast cancer. We found that most breast cancer cell lines expressed both isoforms. Mitogen-dependent pathways concordantly regulated phosphorylation on T389, S371, and T421/S424. Phosphorylation of both isoforms was inhibited by PI3K/mTOR inhibitors. Mitogen-dependent pathways concordantly regulated the phosphorylation of the two isoforms on T389, S371, and T421/S424. Both isoforms had S6 kinase activity. We also detected a p60 isoform with antibodies to the p70(S6K1) C-terminal but not the N-terminal. Further studies on S6K1 isoforms are warranted for therapeutically targeting this pathway.
核糖体蛋白S6激酶1（S6K1）是细胞生长的关键调节因子，在乳腺癌中过度表达，且与预后不良相关。已知S6K1有两种亚型，即p85（S6K1）和p70（S6K1）。p85（S6K1）的特征是在p70（S6K1）的N端额外有23个氨基酸。这被认为可将p85（S6K1）靶向细胞核，而p70（S6K1）主要位于细胞质中。我们试图确定p70（S6K1）和p85（S6K1）在乳腺癌中的激活、调节及功能。我们发现大多数乳腺癌细胞系均表达这两种亚型。丝裂原依赖性途径协同调节T389、S371和T421/S424位点的磷酸化。两种亚型的磷酸化均受到PI3K/mTOR抑制剂的抑制。丝裂原依赖性途径协同调节两种亚型在T389、S371和T421/S424位点的磷酸化。两种亚型均具有S6激酶活性。我们还用针对p70（S6K1）C端而非N端的抗体检测到一种p60亚型。有必要对S6K1亚型进行进一步研究，以便在治疗上靶向该途径。
