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Molecular and Cellular Biology, April 1999, p. 3086-3094, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Modulation of Cell Proliferation by Cytokeratins
K10 and K16
Jesús M.
Paramio,1
M. Llanos
Casanova,1
Carmen
Segrelles,1
Sybille
Mittnacht,2
E. Birgitte
Lane,3 and
José L.
Jorcano1,*
Cell and Molecular Biology Program, CIEMAT,
E-28040 Madrid, Spain,1 and Chester
Beatty Labs, London SW3 6JB,2 and
CRC Cell Structure Group, Department of Anatomy and
Physiology, Medical Science Institute, University of Dundee, Dundee
DD1 4HN, Scotland,3 United Kingdom
Received 8 June 1998/Returned for modification 10 July
1998/Accepted 30 November 1998
The members of the large keratin family of cytoskeletal proteins
are expressed in a carefully regulated tissue- and
differentiation-specific manner. Although these proteins are thought to
be involved in imparting mechanical integrity to
epithelial cells, the functional significance of their complex
differential expression is still unclear. Here we
provide new data suggesting that the expression of particular keratins
may influence cell proliferation. Specifically, we demonstrate that the
ectopic expression of K10 inhibits the proliferation of human
keratinocytes in culture, while K16 expression appears to promote the
proliferation of these cells. Other keratins, such as K13 or K14, do
not significantly alter this parameter. K10-induced inhibition is
reversed by the coexpression of K16 but not that of K14. These results
are coherent with the observed expression pattern of these proteins in
the epidermis: basal, proliferative keratinocytes express K14; when
they terminally differentiate, keratinocytes switch off K14 and start
K10 expression, whereas in response to hyperproliferative stimuli, K16
replaces K10. The characteristics of this process indicate that K10 and K16 act on the retinoblastoma (Rb) pathway, as (i) K10-induced inhibition is hampered by cotransfection with viral oncoproteins which
interfere with pRb but not with p53; (ii) K10-mediated cell growth
arrest is rescued by the coexpression of specific cyclins, cyclin-dependent kinases (CDKs), or cyclin-CDK complexes; (iii) K10-induced inhibition does not take place in Rb-deficient cells but is restored in these cells by cotransfection with pRb or p107 but
not p130; (iv) K16 efficiently rescues the cell growth arrest induced
by pRb in HaCaT cells but not that induced by p107 or p130; and (v) pRb
phosphorylation and cyclin D1 expression are reduced in K10-transfected
cells and increased in K16-transfected cells. Finally, using K10
deletion mutants, we map this inhibitory function to the nonhelical
terminal domains of K10, hypervariable regions in which
keratin-specific functions are thought to reside, and demonstrate that
the presence of one of these domains is sufficient to promote cell
growth arrest.
*
Corresponding author. Mailing address: Department of
Cell and Molecular Biology, CIEMAT, Av. Complutense 22, E-28040 Madrid, Spain. Phone: 34-91-3466598. Fax: 34-91-3466393. E-mail:
jorcano{at}ciemat.es.
Molecular and Cellular Biology, April 1999, p. 3086-3094, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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