Background The PTEN gene encodes a dual lipid and tyrosine phosphatase that regulates signaling through the PI3K/ Akt pathway, and acts as a tumor suppressor protein that is frequently mutated http://www.selleckchem.com/products/PD-0332991.html or deleted in human cancers. Studies have shown that mice heterozygous for PTEN develop spontaneous tumors, and that conditional tissue specific tissue disruption of PTEN leads to tumors in the affected tissues. Through its actions on multi ple downstream signaling proteins, including but not lim ited to the PI3K/Akt pathway, PTEN has the capacity to affect a variety of cancer relevant signaling cascades. Germline mutations of PTEN occur in 80% of patients with Cowden syndrome, which is characterized by the occurrence of multiple non cancerous hamartomas.

in addition, these patients are at high risk for breast, thyroid, and endometrial carcinomas, as well as an increased risk of bladder and renal cell carcinoma. Consistent with these data, PTEN Inhibitors,Modulators,Libraries protein and gene expression have been variously described as reduced, absent, mutated, or deleted in human RCCs. a recent study demonstrated PTEN loss in 20% of RCCs and Inhibitors,Modulators,Libraries another study quoted an LOH of 27% in kidney can cer. Since RCC is a malignancy associated with fre quent treatment failures when metastatic, and because RCC and other tumors lacking PTEN are often resistant to conventional chemotherapy, the mechanism by which PTEN contributes to chemotherapy failure is of immediate clinical importance and may lead to new ther apeutic options for patients with such cancers.

Cell Inhibitors,Modulators,Libraries cycle progression, Inhibitors,Modulators,Libraries both in normal and cancer cells, is finely regulated by the interplay between the cyclins, cyc lin dependent kinases and CDK inhibitors, as well as by fluctuation in their levels at different points Inhibitors,Modulators,Libraries of the cell cycle. The earliest described role of p21 was in cyclin/cdk inhibition, but more recent data also has shown that p21 is involved in positive effects on cyclin/cdk activation through its assembly factor function. In addition, p21 has been shown to be anti apoptotic in many tissues, including cancer, and, as such, has been suggested to be a target for cancer therapy. There are also reports of a role of p21 in inducing senescence, a mechanism which seems to protect against malignant transforma tion. We have previously shown that p21 is a prog nostic marker in clear cell RCC such that its elevated levels portend a poorer prognosis in patients who have metastatic ccRCC at diagnosis.

While p21 is transcriptionally regulated by p53, the mecha nisms that regulate the activity of p21 and its post transla tional modification are less clear. A previous report demonstrated that p21 is phosphorylated by Akt, which leads to increased p21 stability as well as enhanced cell survival, and another report showed that cytoplasmic localization inhibitor Sorafenib of p21 results from HER2/Neu activation of Akt with subsequent p21 phosphorylation.