Unraveling TNF's Role in Celluar Suicide

Unraveling TNF's Role in Cellular Suicide - and Survival

by Jeremy Cherfas

WHAT'S HOT IN BIOLOGY...

Rank	Paper	Citations This Period Mar- Apr 98	Rank Last Period Jan- Feb 98
1	C. Dib, et al. , "A comprehensive genetic map of the human genome based on 5,264 microsatellites," Nature, 380(6570):152-4, 14 March 1996. [Gčnčthon and CNRS URA 1922, Evry, France; INSERM U358, Hosp. Saint-Louis, Paris, France; CHU Laval, Quebec, Canada] *TZ978	70	4
2	C.J. Bult, et al., "Complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii," Science, 273(5278):1058-73, 23 August 1996. <N>[6 U.S. institutions] *VD428	68	5
3	M. Muzio, et al., "FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing sig- naling complex," Cell, 85(6):817-27, 14 June 1996. [U. Michigan Med. Sch., Ann Arbor; German Cancer Res. Ctr., Heidelberg; European Molec. Bio. Lab., Heidelberg; Human Genome Sci., Rockville, MD] *UR604	65	10
4	Y. Feng, et al., "HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor," Science, 272(5263):872-7, 10 May 1996. [NIH, NIAID, Bethesda, MD] *UK757	64	3
5	H. Deng, et al., "Identification of a major co-receptor for primary isolates of HIV-1," Nature, 381(6584):661-6, 20 June 1996. [Howard Hughes Med. Inst., New York U. Med. Ctr., NY; Aaron Diamond AIDS Res. Ctr., Rockefeller U., NY; Stanford U. Med. Ctr., CA; U. Louisville Sch. Med., KY; DNAX Res. Inst., Palo Alto, CA] *UR979	62	1
6	T. Dragic, et al., "HIV-1 entry into CD4⁺ cells is mediated by the chemokine receptor CC-CKR-5," Nature, 381(6584):667-73, 20 June 1996. [Aaron Diamond AIDS Res. Ctr., Rockefeller U., NY; Progenics Pharmaceuticals, Inc., Tarrytown, NY] *UR979	62	2
7	M.P. Boldin, et al., "Involvement of MACH, a novel MORT1/FADD- interacting protease, in Fas/APO-1- and TNF receptor-induced cell death," Cell, 85(6):803-15, 14 June 1996. [Weizmann Inst. Science, Rehovot, Israel] *UR604	49	†
8	G. Alkhatib, et al., "CC CKR5: A RANTES, MIP-1a, MIP-1b receptor as a fusion cofactor for macrophage-tropic HIV-1," Science, 272(5270):1955-8, 28 June 1996. [NIH, NIAID, Bethesda, MD] *UV294	45	6
9	Z.-G. Liu, et al., "Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death," Cell, 87(3):656-76, 1 November 1996. [Univ. Calif., San Diego; Tularik Inc., S. San Francisco, CA] *VQ466	44	†
10	J. Yang, et al., "Prevention of apoptosis by Bcl-2: Release of cythochrome c from mitochondria blocked," Science, 275(5303):1129-32, 21 February 1997. [Emory U., Sch. Med., Atlanta, GA] *WJ503	43	8

SOURCE: ISI's Hot Papers Database. Read the full legend.

Tumor necrosis factor may--finally--be about to live up to its name. TNF is a signal molecule made by the immune system. When it was discovered, more than 20 years ago, its most promising effect was that it caused tumors to shrink. But TNF never fulfilled its early therapeutic promise. Cells developed resistance, and TNF seemed perversely also to help keep cells alive. Now the complexities are being unraveled by researchers pursuing the tangled pathways of programmed cell death, or apoptosis.

Four highly cited papers home in on the ways in which TNF's signals are turned into actions by the cell. Between them, they detail the existence of two separate and independent pathways, one of which causes the cell to suicide while the other talks the cell out of it.

Richard N. Kolesnick's group at Memorial Sloan-Kettering Cancer Center in New York, with their collaborators, started from the observation that different triggers of apoptosis can share downstream elements of the signal pathway. (Their paper--M. Verheij, et al., Nature, 380[6569]:75-9, 1 March 1996--scored 40 citations during March-April and is currently at #12.) Thus TNF and X-rays both generate a secondary messenger called ceramide. Other environmental stresses cause apoptosis via a stress-activated protein kinase (SAPK, probably a Jun-N-terminal kinase). Kolesnick's group showed that ceramide can also activate the SAPK cascade, thus integrating apoptosis caused by environmental factors with that caused by cytokines such as TNF, but saying nothing about how TNF exerts its different effects.

Upstream of ceramide is FLICE, isolated in a technical tour de force led by Marcus Peter and Vishva Dixit (see Science Watch, 8[6]:8, November/December 1997). FLICE (FADD-like interleukin-1[beta]-converting enzyme) turns out to be identical to MACH (MORT1-associating CED homolog), characterized by David Wallach and his group at the Weizmann Institute of Science in Israel. The two papers (Muzio et al., #3, and Boldin et al., #7) were published side by side. Happily, and surely not coincidentally, MACH means "deteriorating" in Hebrew, expressing the authors' conviction that TNF triggers apoptosis through the FLICE/MACH pathway. But TNF also protects cells from apoptosis.

The first clue to the schizophrenic behavior of TNF was that it acts most easily to kill cells in which protein synthesis has been blocked. Cells that are able to make proteins can sometimes withstand the suicide signal of TNF. That means that TNF must itself activate genes that protect the cell from apoptosis. Suspicion fell on nuclear factor kB (NF-kB), which is activated by TNF and is part of the response to stress, inflammation, and infection. David Baltimore's group at MIT showed that mice missing NF-kB die before birth, of what looks like mass suicide by their liver cells, and there were other hints that NF-kB was the cell-saving samaritan. Those hints are confirmed in Baltimore's follow-up paper (see A.A. Beg and D. Baltimore, Science, 274[5288]:782-784, 1 November 1996). Giving NF-kB to deficient cells geatly enhanced their survival when challenged with TNF.

Putting the final touches to current understanding of the dual role of TNF is the paper at #9. Michael Karin, University of California at San Diego, and David Geoddel, Tularik Inc., South San Francisco, dissected the cell's response to TNF. They looked at three cellular responses to TNF: JNK activation, NF-kB activation, and apoptosis.

TNF could induce apoptosis in two ways. One is through interactions between the TNF receptor and other proteins such as FADD, which in turn recruits FLICE/MACH. The other is through a secondary messenger such as ceramide activating JNK, as favored by Kolesnick. Karin's evidence clearly favors the FADD route. In several experiments they triggered apoptosis without activating JNK. That is not to say that JNK is not involved in apoptosis--it clearly is. But it is not essential to TNF-induced apoptosis. TNF also activated NF-kB, but along a different pathway, and the race is on to identify positively the antiapoptotic genes activated by NF-kB.

The therapeutic hope now is that with the links in the chains becoming clearer, drugs can be designed to interfere with specific actions. Thus the resistance of some tumors to TNF may be because they have enhanced NF-kB; blocking it might make the cells susceptible again. Cranking up NF-kB, by contrast, could help protect cells from cytokines in diseases such as rheumatoid arthritis.

Science writer Dr. Jeremy Cherfas
works with the Biotechnology and Biological Sciences
Research Council of the U.K., Swindon.