**Part 2**

**Cancer Signaling, Mechanisms and Targeted Therapy** 

184 Advances in Cancer Therapy

Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P,Isaacs WB,

15;59(22):5830-5.

Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999 Nov

**9**

*1USA 2Japan* 

**Survivin: Identification of Selective** 

**Cells and Identification of a New Splice** 

*2Department of Pediatrics, Shimane University School of Medicine, Shimane* 

**Variant with Growth Survival Activity** 

Louis M. Pelus1 and Seiji Fukuda2 *1Department of Microbiology and Immunology* 

*Indiana University School of Medicine, Indianapolis, IN* 

**Functional Signaling Pathways in Transformed** 

Survivin is a member of the inhibitors of apoptosis (IAP) family of highly conserved proteins implicated in regulation of mitosis, cytokinesis, cell cycle and apoptosis (Altieri, 2003a; Altieri, 2003b; Fukuda & Pelus, 2006). It is expressed during development but down regulated in most adult tissues. However, Survivin is over-expressed in the majority of solid tumors and leukemias, and is usually associated with higher proliferative index, reduced apoptosis, resistance to chemotherapy and increased rate of tumor recurrence, making it an attractive therapeutic target. We have previously shown that Survivin is expressed and growth factor regulated in normal hematopoietic cells and regulates apoptosis and cell cycle entry (Fukuda et al., 2002; Fukuda et al., 2004; Fukuda & Pelus, 2001; Fukuda & Pelus, 2002). Antagonizing Survivin impairs mouse progenitor cell production in vitro (Fukuda et al., 2002; Fukuda et al., 2004) and loss of function upon conditional deletion in vivo leads to bone marrow ablation as a consequence of loss of stem cell function (Leung et al., 2007). While Survivin is tightly regulated in normal hematopoietic cells, deregulated expression is frequently observed in hematologic diseases particularly those characterized by stem cell expansion. Survivin is aberrantly over expressed in acute myeloid leukemia (Adida et al., 2000; Carter et al., 2001) but down regulated in aplastic anemia where hematopoietic stem and progenitor cells are reduced (Badran et al., 2003). It is now clear that Survivin can regulate cell growth under both physiological and pathological conditions. Therefore, identification of differential signaling cascades between normal and abnormal cells downstream of Survivin is required in order to

**2. Survivin mediates aberrant proliferation of hematopoietic progenitor cells** 

Internal tandem duplication (ITD) mutations of the Flt3 tyrosine kinase receptor are found in many patients with acute leukemia, and are an unfavorable prognostic factor (Fukuda et al.,

identify cancer cell specific targets without toxicity to normal cells.

**1. Introduction** 

**transformed by ITD-Flt3** 
