SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

More documents

Recommendations

Info

T U M O R C E L L B I O L O G Y P R O G R A M Dr. Werner’s laboratory also is pursuing the investigation of Ini, a novel transcription factor that is involved in connexin43 gene regulation at the transcriptional level. Knockout experiments in Saccharomyces pombe indicated that the yeast homolog of Ini is an essential protein. It appears to be involved in the mRNA splicing process. SELECTED PUBLICATIONS 2003 Oltra, E, Pfeifer, I, and Werner, R. Ini, a small nuclear protein that enhances the response of the connexin43 gene to estrogen. Endocrinology 144:3148-58, 2003. HIGHLIGHTS/DISCOVERIES • Demonstrated that, in humans, connexin43 is expressed in the heart and the uterus, as well as in many other tissues. Because it is an essential protein (as determined in mice) that affects early development, it is important to understand the mechanisms of its regulation of expression. In the uterus, connexin43 expression is inducible by estrogen. This regulation is clinically important because women who suffer from premature labor also express connexins prematurely. JAMES WYCHE, PH.D. Professor of Biology DESCRIPTION OF RESEARCH One of Dr. Wyche’s interests has been to understand how anti-cancer drugs induce apoptosis (cell deaths) of cancer cells. Recently, he and his colleagues studied how the natural product camptothecin (CPT) and its semi-synthetic derivatives such as CPT-11, 9-amino-CPT (9AC), and 9-nitro-CPT (9NC) induce apoptosis of human colon cancer cells. Many aspects of the mechanism by which these drugs exert their death effect on cancer cells, however, remain largely unknown. In recent years, Dr. Wyche and his colleagues have used a cell model of human colon cancer to demonstrate that treatment with low doses of CPT induces senescence in the presence of a protein call p21. Apoptosis, however, occurs in the absence of p21. Therefore, p21 is a key determinant of the outcome of colon cancer cells treated with CPT drugs at doses that are relevant to clinical application. Thus, CPT treatment of colon cancer cells with p21 should result in disease stabilization, whereas CPT treatment of p21-deficient colon cancer cells should result in rapid apoptosis and disease regression. It is well established that p21 inhibits cyclindependent kinases (Cdks) and several other factors, including proliferating cell nuclear antigens. They hypothesize that inhibition of Cdks by p21 is essential to inhibit apoptosis and induce senescence. In this context, Dr. Wyche and his colleagues propose that a protein named E2F1 is essential for apoptosis of colon cancer cells treated with CPT. According to this hypothesis, inhibition of Cdks should result in activation of another protein, named retinoblastoma (Rb), which in turn, inhibits E2F1 and consequentially E2F1-dependant apoptosis. They also hypothesize that the ability of p21 to induce senescence requires a protein called STAT1. To test their hypothesis, Dr. Wyche’s laboratory currently is using techniques to selectively alter the status of Cdk, E2F1, Rb, and STAT1 genes in human colon cancer cells. They will then investigate the role of each protein in the process of apoptosis and senescence in the colon cancer cells after CPT treatment. The information obtained from these investigations will provide a better insight into the molecular pathways activated in colon cancer cells after CPT treatment and eventually will lead to specific experimental designs to completely understand how CPTs affect colon cancer. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 99
T U M O R C E L L B I O L O G Y P R O G R A M SELECTED PUBLICATIONS 2002 Han, Z, Wei, W, Dunaway, S, Darnowski, JW, Calabresi, P, Sedivy, J, Hendrickson, EA, Balan, KV, Pantazis, P, and Wyche, JH. Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. Journal of Biological Chemistry 277:17154-60, 2002. Han, Z, Ribbizi, I, Pantazis, P, Wyche, J, Darnowski, J, and Calabresi, P. The antibacterial drug taurolidine induces apoptosis by a mitochondrial cytochrome c-dependent mechanism. Anticancer Research 22:1959-64, 2002. 2003 Hu, X, Han, Z, Wyche, JH, and Hendrickson, EA. Helix 6 of tBid is necessary but not sufficient for mitochondrial binding activity. Apoptosis 8:277-89, 2003. Pantazis, P, Han, Z, Balan, K, Wang, Y, and Wyche, JH. Camptothecin and 9- nitrocamptothecin (9NC) and anti-cancer, anti- HIV, and cell-differentiation agents: Development of resistance, enhancement of 9NC-induced activities, and combination treatments in cell and animal models. Anticancer Research 23:3623-38, 2003. Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche, J, Han, Z, and Pantazis, P. Differential susceptibility to 9-nitrocamptothecin (9-NC)-induced apoptosis in clones derived from a human ovarian cancer cell line: possible implications in the treatment of ovarian cancer patients with 9-NC. Anticancer Drugs 14:427-36, 2003. HIGHLIGHTS/DISCOVERIES • The research activities in Dr. Wyche’s laboratory focus on the use of natural products that induce the death of cancer cells. They use several human tumor types, but predominantly colon cancer cells, and exploit substances that damage the cells’ genetic material with a specific effect on killing or controlling the proliferation of theses cells. Current research has led the team to focus on key cellular proteins and manipulation of their genes that may eliminate protein production. They then observe the concomitant impact on cellular functions such as growth or death of the target cancer cell. TERESA A. ZIMMERS, PH.D. Assistant Professor of Surgery DESCRIPTION OF RESEARCH Dr. Zimmers’ research aims to understand the mechanisms regulating tissue homeostasis in order to apply such knowledge to the prevention and treatment of human disease. Recently, she has focused on the roles of the transforming growth factor-beta (TGF-ß) superfamily member—myostatin—in the regulation of skeletal muscle and fat mass. Myostatin is a highly conserved gene expressed at high levels in skeletal muscle and at low levels in white fat. Mice and cattle lacking myostatin function develop skeletal muscle hypertrophy and hyperplasia. Research in Dr. Zimmers’ laboratory has shown that overexpression of myostatin in mice produces hypoglycemia along with a wasting syndrome similar to the cachexia that complicates many chronic diseases such as cancer, AIDS, and organ failure. Concomitant over-expression of the myostatin binding proteins, follistatin and myostatin propeptide, inhibits this wasting, suggesting a means of interfering with endogenous myostatin signaling in animals and patients. 100 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Page 1 and 2:
S C I E N T I F I C R E P O R T 2 0
Page 3 and 4:
I N T R O D U C T I O N A N D P R O
Page 5 and 6:
Page 7 and 8:
Page 9 and 10:
Page 11 and 12:
L E A D E R S H I P MULTIDISCIPLINA
Page 13 and 14:
L E A D E R S H I P EXTERNAL ADVISO
Page 15 and 16:
C A N C E R P R E V E N T I O N A N
Page 17 and 18:
Page 19 and 20:
Page 21 and 22:
Page 23 and 24:
Page 25 and 26:
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36:
Page 37 and 38:
Page 39 and 40:
Page 41 and 42:
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
C L I N I C A L O N C O L O G Y R E
Page 49 and 50:
Page 51 and 52:
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 61 and 62: C L I N I C A L O N C O L O G Y R E
Page 79 and 80: T U M O R C E L L B I O L O G Y P R
Page 111: T U M O R C E L L B I O L O G Y P R
Page 117 and 118: T U M O R I M M U N O L O G Y P R O
Page 143 and 144: V I R A L O N C O L O G Y P R O G R
Page 157 and 158: S H A R E D R E S O U R C E S 3) La
Page 159 and 160: S H A R E D R E S O U R C E S C E L
Page 161 and 162: S H A R E D R E S O U R C E S D N A
Page 163 and 164:
S H A R E D R E S O U R C E S G E N
Page 165 and 166:
S H A R E D R E S O U R C E S I N F
Page 167 and 168:
S H A R E D R E S O U R C E S P O P
Page 169 and 170:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 171 and 172:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 173 and 174:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 175 and 176:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 177 and 178:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 179 and 180:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 181 and 182:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 183 and 184:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 185 and 186:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 187 and 188:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 189 and 190:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 191 and 192:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 193 and 194:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 195 and 196:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 197 and 198:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 199 and 200:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 201 and 202:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 203 and 204:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 205 and 206:
G L O S S A R Y IFN—interferon IL
show all

SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

Create successful ePaper yourself

Delete template?

Save as template?