A Stellar View onSolar Variations and Climate T

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cules that inhibit mitotic entry, anaphase, or the UPS. Verma et al. designed a reporter system consisting of the destruction box do- main of the frog cyclin B1 fused to lu- ciferase, an enzyme that generates a lumi- nescent signal. The authors screened 109,113 small molecules against interphase extracts from frog oocytes for sustained lumines- cence when the extracts were stimulated to enter mitosis. They identified 22 candidate inhibitors of proteolysis. Sixteen of the com- pounds no longer inhibited luciferase degra- dation when added to prestimulated extracts, suggesting that their mode of action may be to inhibit either mitotic entry or APC/C acti- vation. The six remaining compounds were candidates for inhibitors of cyclin B1 degra- dation itself. Three of the compounds also blocked the degradation of β -catenin, a pro- tein that is ubiquitinated by a different E3 lig- ase, indicating that they may be general in- hibitors of ubiquitin-dependent proteolysis.

Importantly, the three compounds that blocked the degradation of cyclin B and β -catenin did not affect either cyclin B ubiquitination or the proteolytic activity of the proteasome core, suggesting that these small molecules blocked an un- known target.

To define the mechanism of inhibition, Verma et al. used a reconstituted UPS system consisting of purified proteasomes and ubiq- uitinated Sic1 (UbSic1), a well-characterized proteasomal substrate that is degraded at the G

- to S-phase transition of the cell cycle in budding yeast (8). Addition of a proteasome inhibitor together with ubistatin A or B did not result in the accumulation of deubiquiti- nated UbSic1. This suggested to the authors that ubistatins appear to act at or upstream of the isopeptidase that removes polyubiquitin before the targeted proteins enter the protea- some core. Indeed, both ubistatins bound di- rectly to polyubiquitin chains as assessed by mobility shift and nuclear magnetic reso- nance experiments, and blocked binding of polyubiquitin to ubiquitin receptor proteins.

In a further validation of substrate specificity, ubistatin A failed to block in vitro proteolysis of ornithine decarboxylase, a ubiquitin-inde- pendent proteasome substrate. Finally, mi- croinjection of ubistatin A into mammalian cells inhibited the degradation of a synthetic UPS substrate. Together, these experiments demonstrate the power of screening in multi- ple model systems where the target pathway is highly conserved.

Verma et al. were able to adopt a rational candidate strategy to determine the mecha- nism of inhibition because their screen was built around a well-characterized cellular pathway. Despite the elegance of this partic- ular example, target identification remains the Achilles’ heel of chemical phenotype screening. Recently, whole-genome reagents,

such as the systematic gene deletion mutants of budding yeast and systematic RNA inter- ference knockdown libraries, have spurred the development of genomic techniques for identifying the targets of small-molecule in- hibitors (9). The advent of techniques for rapid identification of small-molecule targets should encourage a renaissance in forward chemical genetic screening.

The Verma et al. study also raises two important general points. Because the func- tion of the UPS is essential to the cell, it would seem an unlikely therapeutic target.

However, this pathway is under scrutiny by those developing chemotherapeutics be- cause general UPS inhibitors appear to se- lectively kill transformed tumor cells, such as the blood cells involved in multiple myeloma and acute myelogenous leukemia (10). For example, Bortezomib, a protea- some inhibitor that blocks the protease ac- tive site, was recently approved for treating multiple myeloma patients. In addition, pro- teasome inhibitors appear to function as se- lective chemosensitizers or radiosensitizers in a variety of tumor cells (10). The mecha- nism of the enhanced sensitivity of tumor cells to proteasome inhibition is the subject of speculation. Inhibition of the proteasome may subtly alter cell cycle, checkpoint, or

apoptotic networks that rely on UPS-mediat- ed steps. The susceptibility of cancer cells to proteasome inhibition suggests that an at- tack aimed at several networks simultane- ously may be a viable strategy to combat multigenic diseases (11). Finally, the ubis- tatins reinforce the notion that it is indeed possible to disrupt protein-protein interac- tions with small molecules (12). Several oth- er steps in the UPS may also be susceptible to modulation by small molecules (see the figure). In all, this research reveals new op- portunities for developing therapeutics that have targets beyond enzyme active sites, and gets at the very heart of biological specifici- ty, the regulation of protein interactions (13).

References

1. M. Bredel, E. Jacoby,Nature Rev. Genet.5, 262 (2004).

2. R. Vermaet al., Science306, 117 (2004).

3. L. H. Hartwell et al., Science278, 1064 (1997).

4. T. U. Mayer,Trends Cell Biol. 13, 270 (2003).

5. A. Hershko, A. Ciechanover,Ann. Rev. Biochem. 67, 425 (1998).

6. R. W. King et al., Science274, 1652 (1996).

7. J. M. Peters,Mol. Cell9, 931 (2002).

8. R. Verma et al., Cell118, 99 (2004).

9. X. S. Zheng et al., Chem. Biol.11, 609 (2004).

10. J. Adams,Nature Rev. Cancer 4, 349 (2004).

11. J. R. Sharom et al., Curr. Opin. Chem. Biol. 8, 81 (2004).

12. M. R. Arkin, J. A. Wells,Nature Rev. Drug Discov.3, 301 (2004).

13. T. Pawson, P. Nash,Science300, 445 (2003).

T he global warming observed over the past century has been attributed to both natural and human forcings (1). One of the natural forcings may be variations in solar activity, which appear to be correlated with climate change (2). Climate models have used reconstructions of solar irradiance to repro- duce important aspects of past global warm- ing (3). However, recent studies of Sun-like stars call for a reevaluation of the influence of solar activity variations on climate.

Analyses of space-borne solar radiome- try since 1978 [for example, (4)] confirm that the Sun brightens during periods of high activity, when bright magnetic struc- tures more than compensate for the dim- ming caused by sunspots. However, over an 11-year sunspot cycle, the irradiance varies

by only about 0.08%—probably too little for a meaningful influence on climate. The question, then, is whether the sunspot cycle is superimposed on irradiance variations of similar or greater magnitude that take place over periods longer than 11 years.

The apparent identification of a solar component in past climate variations in recent model studies (see the figure) rests on the as- sumption that such variations over longer pe- riods exist. The solar forcing used in these models includes both the sunspot cycle and a more speculative long-term component. The amplitude of this second component is rough- ly five times that of the magnetic modulation during sunspot cycles. It is based on evidence for luminosity variations in Sun-like stars (5) and on a hypothesized long-term relationship between the Sun’s magnetic field and its lu- minosity (6). However, the scientific basis for this component is much less robust than for the sunspot-cycle component.

Stellar observations (5) have suggested that Sun-like stars have low-activity phases

A Stellar View on

Solar Variations and Climate

Peter Foukal, Gerald North, Tom Wigley

P. Foukal is at Heliophysics Inc., Nahant, MA 01908, USA. G. North is in the Department of Atmospheric Sciences, Texas A&M University, College Station, TX 77843, USA. T. Wigley is at the National Center for Atmospheric Research, Boulder, CO 80307, USA. E- mail: pfoukal@world.std.com

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69 during which the magnetic

activity is even lower than during minima in the sunspot cycle. Extrapolation of the Sun’s radiometrically ob- served irradiance to this low- activity level suggests that so- lar irradiance in the 17th cen- tury may have been 0.25%

lower than today (7, 8).

Reconstructions of irradiance variations based directly (7) or indirectly (8) on the stellar evidence have been used in numerous climate studies, some of which form the basis of the Intergovernmental Panel on Climate Change’s conclusions on the relative roles of different external cli- mate forcings (1).

Additional evidence for large multidecadal solar lu- minosity variations came from photometric studies of Sun-like stars, some of which exhibited cyclic vari- ations 3 to 5 times those ob- served radiometrically in the Sun (9). This finding sug-

gested that similarly large luminosity vari- ations may have occurred on the Sun in the recent past. However, concerns were soon raised as to whether the stars studied in (9) and in (5) were truly Sun-like—that is, with very similar mass, age, and chemical composition to the Sun—because the high- dispersion data required for such identifi- cation are relatively difficult to obtain.

Of the stars considered to date, only 18 Scorpii (HR6060) seems to be a sufficient- ly close solar analog for comparison with the Sun’s present irradiance behavior (10).

Furthermore, if the model of Lean et al. (7) correctly describes the Sun’s past activity, it requires disappearance of the prominent photospheric magnetic network as recently as the 1920s (11). This magnetic network was discovered in the early 1890s, and its area has exhibited no significant changes since at least 1915. The model is therefore unlikely to be correct.

Recent results raise further concerns about the scientific basis of the irradiance re- constructions used in recent climate models.

First, the bimodal distribution of stellar mag- netic activity cited in (5) as evidence for low- activity phases in Sun-like stars is not found when more homogeneous samples of stars are studied in more detail (12, 13). Second, wide-band photometry of 18 solar analogs (14) shows no evidence of luminosity varia- tions greater than 0.05%. The data so far do not support the earlier conclusion that the Sun’s irradiance variability of 0.08% is lower

than that of similar stars. Searches for large- amplitude multidecadal variations in solar output have also been unsuccessful (15).

A further claim that the 11-year sunspot cycle might be superimposed on substan- tial long-term variations comes from varia- tions in the interplanetary magnetic field (IMF) identified in the “aa” index, a daily and half-daily index of geomagnetic activi- ty that dates back to 1868 (6, 16). The IMF is a measure of changes in the “open” mag- netic flux of the Sun. These changes have, in turn, a statistical relationship with solar irradiance variations. The aa index in- creased gradually between 1900 and about 1955, possibly indicating a decadal-time- scale increase in irradiance. However, both the data calibration and the connection to irradiance variations (17) have been ques- tioned. Furthermore, the statistical rela- tionship between the IMF and irradiance is significant only on the monthly time scale, not on the interannual time scale. Any rela- tionship on longer time scales must there- fore remain speculative.

The reason for the apparent constancy of the Sun’s luminosity, despite its vigorous convection, is probably the enormous ther- mal inertia of atmospheric layers below the shallow photosphere. Without this inertia, the large irradiance fluctuations caused by spots and faculae would be rapidly canceled by compensating temperature variations outside these localized structures (15).

Lean et al. recently accepted (17) that

the long-term irradiance variations used in climate models in the past decade may be a factor of ~5 larger than can be justified.

The full impact of this changed outlook on attempts to explain past climate variations and estimates of climate sensitivity to ex- ternal forcing remains to be seen.

Some recent climate models incorpo- rate the possible effects of solar ultraviolet (UV) flux variations on climate via their effect on stratospheric ozone, which might influence the propagation of planetary waves and hence the latitudinal heat distri- bution in the troposphere. However, the correlation between 20th-century global temperature changes and a reconstruction of UV flux is relatively low (18). It is therefore unclear whether UV effects can add significantly to the strength of the di- rect solar irradiance changes usually con- sidered in climate modeling. Other studies suggesting that solar plasma and field out- puts (including cosmic ray influences) might affect climate remain speculative.

The absence of convincing evidence does not rule out long-term luminosity variations of the Sun. It does, however, em- phasize the need for more reproducible so- lar radiometry, more accurate photometry, and studies of larger samples of Sun-like stars. New technologies—including cryo- genic radiometers, thermal imagers, and automated photometric telescopes—are now available to provide these advances. It should then be possible to move beyond modeling based on speculative irradiance changes toward a more physically based understanding of Sun-climate relations.

References and Notes

1. J. T. Houghton et al., Eds., Climate Change 2001: The Scientific Basis (Cambridge Univ. Press, Cambridge, 2001).

2. T. Crowley,Science 289, 270 (2000).

3. P. A. Stott et al., Clim. Dyn.17, 1 (2001).

4. C. Fröhlich, J. Lean,Geophys. Res. Lett.25, 4377 (1998).

5. S. Baliunas, R. Jastrow,Nature 348, 520 (1990).

6. M. Lockwood, R. Stamper, M. N. Wild,Nature399, 437 (1999).

7. J. Lean, J. Beer, R. Bradley,Geophys. Res. Lett. 22, 3195 (1995).

8. D. Hoyt, K. Schatten,J. Geophys. Res.98, 18895 (1993).

9. G. W. Lockwoodet al., Nature360, 653 (1992).

10. G. F Porto de Mello, L. da Silva,Astrophys. J. 482, L89 (1997).

11. P. Foukal, L. Milano,Geophys. Res. Lett.28, 883 (2001).

12. M. Giampapa et al., in preparation.

13. J. Hall, G. W. Lockwood,Astrophys. J., in press.

14. G. Henry, in preparation.

15. P. Foukal,Eos84, 205 (2003).

16. M. Lockwood, R. Stamper,Geophys. Res. Lett.26, 2461 (1999).

17. J. Lean, Y. Wang, N. Sheeley,Geophys. Res. Lett.29, 2224 (2002).

18. P. Foukal,Geophys. Res. Lett.29, 2089 (2002).

19. T. M. L. Wigley, S. C. B. Raper,Science293, 451 (2001).

20. We thank M. Giampapa, J. Hall, and G. Henry for per- mission to cite and discuss their results prior to pub- lication. We also thank J. Eddy, C. Fröhlich, J. Leibacher, and M. Schlesinger for helpful comments. P.F.'s work on this article was supported by NSF grant ATM 0303557 and NASA grant NNG04GN41G, both to Heliophysics, Inc.

–0.08–0.1 –0.06 –0.04 –0.020.020.040.060.080 0.120.14 0.1

1600 1650 1700 1750 1800 Year

1850 1900 1950 2000 1600 1650 1700 1750 1800 1850 1900 1950 2000 Top of atmosphere radiative forcing (W/m2)

–0.2 –0.1 0 0.1 0.2 0.3 0.4

Global-mean temperature (°C)

Apparent magnitude of solar forcings.

(Top) Top-of-atmosphere so- lar forcing (red) from ( 7 ), showing the sunspot cycle component sepa- rately (blue). (Bottom) Global-mean temperature responses to the forc- ings shown in the top panel, calculated with the MAGICC climate mod- el using best estimate parameters ( 19 ). Forcings and responses are ze- roed in 1900. The temperature response to the speculative long-term component is much larger than to the sunspot-cycle component alone.

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