Forefronts in Nephrology1188

of Cancer (vol 1), edited by Bertino JR, San Diego, Academic 6. Foley KP, McArthur GA, Queva C, Hurlin PJ, Soriano P, Eisen-man RN: Targeted disruption of the Myc antagonist Madl inhibitsPress, 1997, pp 419–431

4. Laherty CD, Yang W-M, Sun J-M, Davie JR, Seto E, Eisenman cell cycle exit during granulocyte differentiation. EMBO J 17:774–785, 1998RN: Histone deacetylases associated with the mSin3 corepressor

mediate Mad transcriptional repression. Cell 82:349–356, 1997 7. Queva C, Hurlin PJ, Foley KP, Eisenman RN: Sequential expres-sion of the MAD family of transcriptional repressors during differ-5. Grandori C, Eisenman RN: Myc target genes. Trends Biochem Sci

22:177–181, 1997 entiation and development. Oncogene 16:967–977, 1998

Extracellular matrix and integrin-signaling in the regulation ofcell growth

RICHARD K. ASSOIAN

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

The extracellular matrix (ECM) and mitogenic growth Finally, we find that mitogen-activated protein (MAP)kinase is responsible for the growth factor-stimulatedfactors are jointly required for cell cycle progression

through G1 phase, and this combined requirement is expression of p21, but we also find that this inductiondoes not require the sustained activation of MAP kinase.manifest in the regulation of the G1-phase cyclins and

cyclin dependent kinase (CDK) inhibitors. One of the To our knowledge, this is the first report of a functionallysignificant cell cycle effect that is mediated by the tran-G1-phase cell cycle events regulated by cell adhesion is

the expression of the CDK inhibitor p21. p21 is induced sient induction of MAP kinase.in early G1 phase, and this induction may play a role in

REFERENCESassembling cyclin-CDK complexes. Down-regulation ofp21 then occurs in mid-late G1, coincident with the acti- 1. Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK: Adhe-

sion-dependent cell cycle progression linked to the expression ofvation of G1-phase cyclin-CDKs. We have examined thecyclin D1, activation of cyclin E-cdk2, and phosphorylation of therelative contributions of both mitogens and the ECM inretinoblastoma protein. J Cell Biol 133:391–403, 1996

the regulation of p21. Our results show that p21 expres- 2. Assoian RK, Zhu X: Cell anchorage and the cytoskeleton as part-ners in growth factor dependent cell cycle progression. Curr Opinsion can be divided into two discrete phases: The rapidCell Biol 9:93–98, 1997up-regulation is strongly dependent on mitogens, 3. Assoian RK, Marcantonio EE: The extracellular matrix as a cell

whereas the subsequent down-regulation is strongly de- cycle control element in atherosclerosis and restenosis. J Clin Invest100(Suppl):S15–S18, 1997pendent on cell anchorage. Comparative studies with

4. Bohmer RM, Scharf E, Assoian RK: Cytoskeletal integrity is re-wild-type and p21-null fibroblasts confirm that this ECM- quired throughout the mitogen stimulation phase of the cell cycledependent repression of p21 is important for proper con- and mediates the anchorage-dependent expression of cyclin D1.

Mol Biol Cell 7:101–111, 1997trol of cyclin E-CDK2. We also find that the growth5. Bottazzi ME, Assoian RK: The extracellular matrix and mitogenicfactor-dependent induction of p21 contributes to the tim- growth factors control G1 phase cyclins and cyclin-dependent kinase

ing of pRb phosphorylation and expression of cyclin A. inhibitors. Trends Cell Biol 7:348–352, 1997

Forefronts in Nephrology 1189

The adapter protein Shc couples a class of integrins to thecontrol of the cell cycle

FILIPPO G. GIANCOTTI,1 KISHORE K. WARY, and FABRIZIO MAINIERO

Memorial Sloan Kettering Cancer Center, New York, New York, USA

For proper embryonic development and tissue homeo- integrins with Shc, mediated by caveolin-1 and Fyn, isnecessary and sufficient to activate the Ras-Erk signalingstasis, cell proliferation must be regulated spatially andpathway. In contrast, activation of focal adhesion kinasetemporally. In particular, a cell must be able to sense itsdoes not cause this event. Although ligation of integrinsrelationship to other cells and the extracellular matrixlinked to Shc allows primary endothelial cells to progressand convert these positional cues into biochemical sig-through G1 in response to mitogens, ligation of othernals affecting the cell cycle machinery. The importanceintegrins causes exit from the cell cycle and, in the ab-of the extracellular matrix in cell cycle control is under-sence of intercellular contact, apoptotic death. Thus, thescored by the observation that normal fibroblasts needcoupling of specific integrins to Shc may function as ato adhere to serum-derived extracellular matrix proteinsswitch that controls cell survival and cell cycle progres-in order to proliferate in vitro, a phenomenon calledsion in response to the extracellular matrix. Because exitanchorage dependence. Neoplastic cells are no longerfrom the cell cycle is a prerequisite for cell differentia-sensitive to the growth control exerted by the extracellu-tion, these results may also explain why in some settingslar matrix, and this property is likely to contribute sig-interaction with the extracellular matrix promotes differ-nificantly to their ability to invade and metastasize. Uponentiation.binding to components of the extracellular matrix, inte-

grins interact with cytoskeletal and signaling molecules.REFERENCESStudies in our laboratory have indicated that a class of1. Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancottiintegrins recruit the signaling protein Shc. Shc is an SH2-

FG: The adaptor protein Shc couples a class of integrins to thePTB domain adaptor that links various tyrosine kinases control of cell cycle progression. Cell 87:733–743, 1996to Ras by recruiting the Grb2/mSOS complex to the 2. Giancotti FG: Integrin signaling: Specificity and control of cell

survival and cell cycle progression. Curr Opin Cell Biol 9:691–700,plasma membrane. Although Shc can bind directly to1997

the tyrosine-phosphorylated cytoplasmic domain of a6b4, 3. Mainiero F, Murgia C, Wary KK, Curatola AM, Pepe A, Blu-memberg M, Der Westwick JKCJ, Giancotti FG: The coupling ofthe recruitment of Shc to other integrins is indirect anda8b4 integrin to Ras-MAP kinase pathways mediated by Shc controlsmediated by the interaction of their a subunit withkeratinocyte proliferation. EMBO J 16:2365–2375, 1997

caveolin-1 and thereby Fyn. Mutagenesis and dominant 4. Wary KK, Mariotti A, Zurzolo C, Giancotti FG: A requirementfor caveolin-1 and associated kinase Fyn in integrin signaling andnegative studies indicate that the association of specificanchorage-dependent cell growth. Cell 94:625–634, 1998

5. Pozzi A, Wary KK, Giancotti FG, Gardner HA: Integrin alpha1beta1 mediates a unique collagen-dependent proliferation pathway

1 Speaker and participant in vivo. J Cell Biol 142:587–594, 1998